rs374648988

Variant names:

• chr19-11060161-G-A
• rs374648988
• NM_001387283.1:c.4981G>A
• SMARCA4 p.Asp1661Asn

Your query was ambiguous. Multiple possible variants found:

• chr19-11060161-G-A
• chr19-11060161-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS1

The NM_003072.5(SMARCA4):​c.4885G>A​(p.Asp1629Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,551,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D1629D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 7.93
• Publications: 2 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4115793).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000055 (77/1398808) while in subpopulation NFE AF = 0.0000677 (73/1078666). AF 95% confidence interval is 0.000055. There are 0 homozygotes in GnomAdExome4. There are 33 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

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.4981G>A	p.Asp1661Asn	missense	Exon 35 of 36	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.4885G>A	p.Asp1629Asn	missense	Exon 34 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.4981G>A	p.Asp1661Asn	missense	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.4981G>A	p.Asp1661Asn	missense	Exon 35 of 36	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.4885G>A	p.Asp1629Asn	missense	Exon 34 of 35	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.4891G>A	p.Asp1631Asn	missense	Exon 34 of 35	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000129 AC: 2 AN: 155394 AF XY: 0.0000122

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: 0.0000335

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000550 AC: 77 AN: 1398808 Hom.: 0 Cov.: 33 AF XY: 0.0000478 AC XY: 33 AN XY: 689946

African (AFR) AF: 0.00 AC: 0 AN: 31580

American (AMR) AF: 0.00 AC: 0 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.0000677 AC: 73 AN: 1078666

Other (OTH) AF: 0.0000518 AC: 3 AN: 57960

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	2	-	not provided (2)
-	1	-	Intellectual disability, autosomal dominant 16 (1)
-	1	-	Rhabdoid tumor predisposition syndrome 2 (1)
-	1	-	SMARCA4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Benign	0.41
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.35
Sift	Benign	0.46	T
Sift4G	Benign	0.070	T
Varity_R		0.16
gMVP		0.73
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs374648988;

hg19: chr19-11170837;