rs770680174

Variant names:

• chr19-11033351-G-A
• rs770680174
• NM_001387283.1:c.3608G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11033351-G-A
• chr19-11033351-G-C
• chr19-11033351-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001387283.1(SMARCA4):​c.3608G>A​(p.Arg1203His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1203C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 9.66
• Publications: 8 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11033350-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2780427.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 19-11033351-G-A is Pathogenic according to our data. Variant chr19-11033351-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 449452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3608G>A	p.Arg1203His	missense_variant	Exon 27 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3608G>A	p.Arg1203His	missense_variant	Exon 26 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3608G>A	p.Arg1203His	missense_variant	Exon 27 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3020G>A	p.Arg1007His	missense_variant	Exon 23 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2252G>A	p.Arg751His	missense_variant	Exon 19 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2333G>A	p.Arg778His	missense_variant	Exon 19 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2093G>A	p.Arg698His	missense_variant	Exon 18 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1961G>A	p.Arg654His	missense_variant	Exon 17 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.-137G>A		upstream_gene_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250950 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460922 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726754

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 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: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Feb 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2022

GeneDx

Significance: Pathogenic

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; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25168959, 24090879, 25326635, 23929686, 24658002) -

Intellectual disability, autosomal dominant 16 Pathogenic:1 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Likely pathogenicity based on finding it once in our laboratory de novo in a 2-year-old male with global delays, agenesis of the corpus callosum, hypoplastic cerebellar vermis, cleft palate, Pierre-Robin, apnea, GERD, growth failure, ptosis, pyloric stenosis, dysmorphisms, microcephaly, hypoplastic 4th & 5th nails -

SMARCA4-related BAFopathy Pathogenic:1

Jun 10, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.;.;.;.
PhyloP100		9.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.3	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.
Polyphen		0.99	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.
Vest4		0.97
MutPred		0.82		Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);.;Loss of MoRF binding (P = 0.0464);.;.;.;
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		-0.0082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs770680174; hg19: chr19-11144027; COSMIC: COSV60803832; COSMIC: COSV60803832;