19-11003063-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001387283.1(SMARCA4):​c.1847C>T​(p.Pro616Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P616S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

6
8
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.91

Publications

5 publications found
Variant links:
Genes affected
SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
SMARCA4 Gene-Disease associations (from GenCC):
  • Coffin-Siris syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
  • intellectual disability, autosomal dominant 16
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • rhabdoid tumor predisposition syndrome 2
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
  • uterine corpus sarcoma
    Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
  • familial rhabdoid tumor
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary nonpolyposis colon cancer
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000329 (5/152170) while in subpopulation AFR AF = 0.0000965 (4/41432). AF 95% confidence interval is 0.0000325. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMARCA4NM_001387283.1 linkc.1847C>T p.Pro616Leu missense_variant Exon 12 of 36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkc.1847C>T p.Pro616Leu missense_variant Exon 12 of 35 ENST00000344626.10 NP_003063.2 P51532-1A7E2E1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMARCA4ENST00000646693.2 linkc.1847C>T p.Pro616Leu missense_variant Exon 12 of 36 NM_001387283.1 ENSP00000495368.1 Q9HBD4
SMARCA4ENST00000344626.10 linkc.1847C>T p.Pro616Leu missense_variant Exon 12 of 35 1 NM_003072.5 ENSP00000343896.4 P51532-1
SMARCA4ENST00000643549.1 linkc.1847C>T p.Pro616Leu missense_variant Exon 12 of 35 ENSP00000493975.1 A0A2R8Y4P4
SMARCA4ENST00000541122.6 linkc.1847C>T p.Pro616Leu missense_variant Exon 13 of 35 5 ENSP00000445036.2 P51532-4
SMARCA4ENST00000643296.1 linkc.1847C>T p.Pro616Leu missense_variant Exon 12 of 34 ENSP00000496635.1 P51532-4
SMARCA4ENST00000644737.1 linkc.1847C>T p.Pro616Leu missense_variant Exon 12 of 34 ENSP00000495548.1 P51532-4
SMARCA4ENST00000589677.5 linkc.1847C>T p.Pro616Leu missense_variant Exon 13 of 35 5 ENSP00000464778.1 P51532-3
SMARCA4ENST00000643995.1 linkc.1259C>T p.Pro420Leu missense_variant Exon 9 of 32 ENSP00000496004.1 A0A2R8YGG3
SMARCA4ENST00000644963.1 linkc.491C>T p.Pro164Leu missense_variant Exon 5 of 28 ENSP00000495599.1 A0A2R8YG32
SMARCA4ENST00000644065.1 linkc.572C>T p.Pro191Leu missense_variant Exon 5 of 27 ENSP00000493615.1 A0A2R8Y440
SMARCA4ENST00000642350.1 linkc.332C>T p.Pro111Leu missense_variant Exon 4 of 27 ENSP00000495355.1 A0A2R8Y6N0
SMARCA4ENST00000643857.1 linkc.200C>T p.Pro67Leu missense_variant Exon 3 of 25 ENSP00000494159.1 A0A2R8Y526

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152170
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000239
AC:
6
AN:
251452
AF XY:
0.0000221
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000383
AC:
56
AN:
1461788
Hom.:
0
Cov.:
33
AF XY:
0.0000440
AC XY:
32
AN XY:
727200
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000486
AC:
54
AN:
1111936
Other (OTH)
AF:
0.00
AC:
0
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
4
8
13
17
21
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
African (AFR)
AF:
0.0000965
AC:
4
AN:
41432
American (AMR)
AF:
0.00
AC:
0
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4838
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2
Jan 21, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 616 of the SMARCA4 protein (p.Pro616Leu). This variant is present in population databases (rs755935365, gnomAD 0.008%). This missense change has been observed in individual(s) with neurodevelopmental disorders (PMID: 37500730). ClinVar contains an entry for this variant (Variation ID: 470263). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dec 23, 2023
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Jan 29, 2021
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jan 21, 2022
Sema4, Sema4
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:curation

- -

Intellectual disability, autosomal dominant 16 Uncertain:1
Jul 15, 2021
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Mar 21, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24658002) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.64
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Uncertain
0.63
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.61
T
MutationAssessor
Benign
2.0
M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.;.;.;.
PhyloP100
7.9
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-4.1
D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;N;D;.;.;.
REVEL
Uncertain
0.30
Sift
Benign
0.041
D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;T;D;.;.;.
Sift4G
Benign
0.15
T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.
Polyphen
0.99
D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.
Vest4
0.93
MVP
0.92
MPC
2.5
ClinPred
0.88
D
GERP RS
4.6
PromoterAI
0.018
Neutral
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.8
Varity_R
0.24
gMVP
0.89
Mutation Taster
=38/62
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs755935365; hg19: chr19-11113739; COSMIC: COSV60800813; COSMIC: COSV60800813; API