19-10996314-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_003072.5(SMARCA4):​c.1695G>C​(p.Thr565Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

SMARCA4
NM_003072.5 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -5.76
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
Variant 19-10996314-G-C is Benign according to our data. Variant chr19-10996314-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2587118.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMARCA4NM_001387283.1 linkc.1695G>C p.Thr565Thr synonymous_variant Exon 10 of 36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkc.1695G>C p.Thr565Thr synonymous_variant Exon 10 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.1695G>C p.Thr565Thr synonymous_variant Exon 10 of 36 NM_001387283.1 ENSP00000495368.1 Q9HBD4
SMARCA4ENST00000344626.10 linkc.1695G>C p.Thr565Thr synonymous_variant Exon 10 of 35 1 NM_003072.5 ENSP00000343896.4 P51532-1
SMARCA4ENST00000643549.1 linkc.1695G>C p.Thr565Thr synonymous_variant Exon 10 of 35 ENSP00000493975.1 A0A2R8Y4P4
SMARCA4ENST00000541122.6 linkc.1695G>C p.Thr565Thr synonymous_variant Exon 11 of 35 5 ENSP00000445036.2 P51532-4
SMARCA4ENST00000643296.1 linkc.1695G>C p.Thr565Thr synonymous_variant Exon 10 of 34 ENSP00000496635.1 P51532-4
SMARCA4ENST00000644737.1 linkc.1695G>C p.Thr565Thr synonymous_variant Exon 10 of 34 ENSP00000495548.1 P51532-4
SMARCA4ENST00000589677.5 linkc.1695G>C p.Thr565Thr synonymous_variant Exon 11 of 35 5 ENSP00000464778.1 P51532-3
SMARCA4ENST00000643995.1 linkc.1107G>C p.Thr369Thr synonymous_variant Exon 7 of 32 ENSP00000496004.1 A0A2R8YGG3
SMARCA4ENST00000644963.1 linkc.339G>C p.Thr113Thr synonymous_variant Exon 3 of 28 ENSP00000495599.1 A0A2R8YG32
SMARCA4ENST00000644065.1 linkc.423G>C p.Thr141Thr synonymous_variant Exon 3 of 27 ENSP00000493615.1 A0A2R8Y440
SMARCA4ENST00000642350.1 linkc.183G>C p.Thr61Thr synonymous_variant Exon 2 of 27 ENSP00000495355.1 A0A2R8Y6N0
SMARCA4ENST00000643857.1 linkc.48G>C p.Thr16Thr synonymous_variant Exon 1 of 25 ENSP00000494159.1 A0A2R8Y526

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152234
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
33
GnomAD4 genome
AF:
0.00000656
AC:
1
AN:
152352
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1
Jun 24, 2023
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.87
CADD
Benign
0.15
DANN
Benign
0.67
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
3.9

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1173206989; hg19: chr19-11106990; API