rs7935

Variant names:

• chr19-10994932-T-C
• rs7935
• NM_001387283.1:c.1524T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003072.5(SMARCA4):​c.1524T>C​(p.His508His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,613,226 control chromosomes in the GnomAD database, including 100,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8201 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92385 hom.)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.80
• Publications: 42 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 19-10994932-T-C is Benign according to our data. Variant chr19-10994932-T-C is described in ClinVar as Benign. ClinVar VariationId is 126359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003072.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	NM_001387283.1	MANE Plus Clinical	c.1524T>C	p.His508His	synonymous	Exon 9 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.1524T>C	p.His508His	synonymous	Exon 9 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.1524T>C	p.His508His	synonymous	Exon 9 of 36	NP_001122321.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.1524T>C	p.His508His	synonymous	Exon 9 of 36	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.1524T>C	p.His508His	synonymous	Exon 9 of 35	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.1524T>C	p.His508His	synonymous	Exon 9 of 35	ENSP00000493975.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49334 AN: 151958 Hom.: 8181 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.328 AC: 82139 AN: 250764 AF XY: 0.339

Gnomad AFR exome AF: 0.302

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.340

Gnomad EAS exome AF: 0.235

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.351

Gnomad OTH exome AF: 0.346

GnomAD4 exome AF: 0.352 AC: 514614 AN: 1461150 Hom.: 92385 Cov.: 37 AF XY: 0.355 AC XY: 258355 AN XY: 726880

African (AFR) AF: 0.305 AC: 10196 AN: 33466

American (AMR) AF: 0.197 AC: 8799 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 8988 AN: 26134

East Asian (EAS) AF: 0.226 AC: 8980 AN: 39696

South Asian (SAS) AF: 0.433 AC: 37300 AN: 86230

European-Finnish (FIN) AF: 0.361 AC: 19260 AN: 53388

Middle Eastern (MID) AF: 0.386 AC: 2226 AN: 5768

European-Non Finnish (NFE) AF: 0.358 AC: 398035 AN: 1111428

Other (OTH) AF: 0.345 AC: 20830 AN: 60368

GnomAD4 genome AF: 0.325 AC: 49391 AN: 152076 Hom.: 8201 Cov.: 32 AF XY: 0.326 AC XY: 24220 AN XY: 74338

African (AFR) AF: 0.304 AC: 12612 AN: 41482

American (AMR) AF: 0.238 AC: 3639 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1216 AN: 3472

East Asian (EAS) AF: 0.244 AC: 1254 AN: 5148

South Asian (SAS) AF: 0.413 AC: 1990 AN: 4822

European-Finnish (FIN) AF: 0.368 AC: 3895 AN: 10582

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.349 AC: 23708 AN: 67988

Other (OTH) AF: 0.321 AC: 677 AN: 2106

Alfa AF: 0.340 Hom.: 40294

Bravo AF: 0.312

Asia WGS AF: 0.333 AC: 1158 AN: 3478

EpiCase AF: 0.362

EpiControl AF: 0.353

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Coffin-Siris syndrome (1)
-	-	1	Intellectual disability, autosomal dominant 16 (1)
-	-	1	not provided (1)
-	-	1	Rhabdoid tumor predisposition syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.065
DANN	Benign	0.39
PhyloP100		-1.8
PromoterAI		0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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: rs7935; hg19: chr19-11105608; COSMIC: COSV60787320; COSMIC: COSV60787320;