rs7275

Variant names:

• chr19-11060163-T-C
• rs7275
• NM_001387283.1:c.4983T>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.4887T>C​(p.Asp1629Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,551,084 control chromosomes in the GnomAD database, including 69,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6233 hom., cov: 33)
  • Exomes 𝑓: 0.30 (63680 hom.)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.51
• Publications: 38 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: Orphanet, ClinGen, 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: G2P, Ambry Genetics, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• otosclerosis

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• 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: Unknown 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=-0.72).
• BP6: Variant 19-11060163-T-C is Benign according to our data. Variant chr19-11060163-T-C is described in ClinVar as Benign. ClinVar VariationId is 126365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.317 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.4983T>C	p.Asp1661Asp	synonymous	Exon 35 of 36	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.4887T>C	p.Asp1629Asp	synonymous	Exon 34 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.4983T>C	p.Asp1661Asp	synonymous	Exon 35 of 36	NP_001122321.1	Q9HBD4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.4983T>C	p.Asp1661Asp	synonymous	Exon 35 of 36	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.4887T>C	p.Asp1629Asp	synonymous	Exon 34 of 35	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.4893T>C	p.Asp1631Asp	synonymous	Exon 34 of 35	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42769 AN: 152018 Hom.: 6231 Cov.: 33

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.0912

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.265

GnomAD2 exomes AF: 0.261 AC: 40606 AN: 155306 AF XY: 0.271

Gnomad AFR exome AF: 0.300

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.249

Gnomad EAS exome AF: 0.0819

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.297 AC: 416170 AN: 1398948 Hom.: 63680 Cov.: 38 AF XY: 0.299 AC XY: 206524 AN XY: 690000

African (AFR) AF: 0.300 AC: 9464 AN: 31580

American (AMR) AF: 0.167 AC: 5951 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 6393 AN: 25170

East Asian (EAS) AF: 0.0895 AC: 3198 AN: 35732

South Asian (SAS) AF: 0.347 AC: 27510 AN: 79216

European-Finnish (FIN) AF: 0.233 AC: 11462 AN: 49182

Middle Eastern (MID) AF: 0.298 AC: 1667 AN: 5588

European-Non Finnish (NFE) AF: 0.309 AC: 333615 AN: 1078814

Other (OTH) AF: 0.292 AC: 16910 AN: 57968

GnomAD4 genome AF: 0.281 AC: 42797 AN: 152136 Hom.: 6233 Cov.: 33 AF XY: 0.276 AC XY: 20553 AN XY: 74386

African (AFR) AF: 0.303 AC: 12584 AN: 41510

American (AMR) AF: 0.213 AC: 3264 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 898 AN: 3472

East Asian (EAS) AF: 0.0912 AC: 471 AN: 5166

South Asian (SAS) AF: 0.330 AC: 1593 AN: 4820

European-Finnish (FIN) AF: 0.231 AC: 2443 AN: 10584

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20609 AN: 67978

Other (OTH) AF: 0.264 AC: 556 AN: 2106

Alfa AF: 0.292 Hom.: 18668

Bravo AF: 0.279

Asia WGS AF: 0.224 AC: 782 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Coffin-Siris syndrome (1)
-	-	1	Hereditary cancer-predisposing 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	-0.72
CADD	Benign	0.13
DANN	Benign	0.54
PhyloP100		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs7275; hg19: chr19-11170839; COSMIC: COSV60786038; COSMIC: COSV60786038;