rs1060502071

Variant names:

• chr19-10986593-G-A
• rs1060502071
• NM_001387283.1:c.760G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-10986593-G-A
• chr19-10986593-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_003072.5(SMARCA4):​c.760G>A​(p.Gly254Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.88

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.760G>A	p.Gly254Ser	missense_variant, splice_region_variant	Exon 4 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.760G>A	p.Gly254Ser	missense_variant, splice_region_variant	Exon 4 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.760G>A	p.Gly254Ser	missense_variant, splice_region_variant	Exon 4 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.760G>A	p.Gly254Ser	missense_variant, splice_region_variant	Exon 4 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.760G>A	p.Gly254Ser	missense_variant, splice_region_variant	Exon 4 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.760G>A	p.Gly254Ser	missense_variant, splice_region_variant	Exon 5 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.760G>A	p.Gly254Ser	missense_variant, splice_region_variant	Exon 4 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.760G>A	p.Gly254Ser	missense_variant, splice_region_variant	Exon 4 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.760G>A	p.Gly254Ser	missense_variant, splice_region_variant	Exon 5 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.172G>A	p.Gly58Ser	missense_variant, splice_region_variant	Exon 1 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:1

Jan 30, 2024

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.38 (>=0.2, moderate evidence for spliceogenicity)]. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Dec 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 254 of the SMARCA4 protein (p.Gly254Ser). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 408625). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.5	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.3	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.16	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.32	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D
Vest4		0.83
MutPred		0.28		Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);Gain of phosphorylation at G254 (P = 0.0033);
MVP		0.78
MPC		0.90
ClinPred		0.88	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.13
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: 26

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060502071; hg19: chr19-11097269;