rs767947665

Variant names:

• chr19-10986973-C-G
• rs767947665
• NM_001387283.1:c.829C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-10986973-C-G
• chr19-10986973-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001387283.1(SMARCA4):​c.829C>G​(p.Pro277Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P277S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.500
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050736457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.829C>G	p.Pro277Ala	missense_variant	Exon 5 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.829C>G	p.Pro277Ala	missense_variant	Exon 5 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.829C>G	p.Pro277Ala	missense_variant	Exon 5 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.829C>G	p.Pro277Ala	missense_variant	Exon 5 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.829C>G	p.Pro277Ala	missense_variant	Exon 5 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.829C>G	p.Pro277Ala	missense_variant	Exon 6 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.829C>G	p.Pro277Ala	missense_variant	Exon 5 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.829C>G	p.Pro277Ala	missense_variant	Exon 5 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.829C>G	p.Pro277Ala	missense_variant	Exon 6 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.241C>G	p.Pro81Ala	missense_variant	Exon 2 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455682 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724466

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111836

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.26	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.92	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.051	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	-0.11	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.
PhyloP100		0.50
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.080	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Benign	0.17
Sift	Benign	0.39	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.63	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B
Vest4		0.31
MutPred		0.23		Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);Loss of glycosylation at P277 (P = 0.0298);
MVP		0.40
MPC		0.26
ClinPred		0.11	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.032
gMVP		0.048
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs767947665; hg19: chr19-11097649;