NM_001387283.1:c.4840G>A

Variant names:

• chr19-11059861-G-A
• rs768899897
• NM_001387283.1:c.4840G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001387283.1(SMARCA4):​c.4840G>A​(p.Glu1614Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,848 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).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.27

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_benign. Variant got -5 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24684909).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4840G>A	p.Glu1614Lys	missense_variant	Exon 34 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4744G>A	p.Glu1582Lys	missense_variant	Exon 33 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4840G>A	p.Glu1614Lys	missense_variant	Exon 34 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4744G>A	p.Glu1582Lys	missense_variant	Exon 33 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4750G>A	p.Glu1584Lys	missense_variant	Exon 33 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4654G>A	p.Glu1552Lys	missense_variant	Exon 33 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4654G>A	p.Glu1552Lys	missense_variant	Exon 32 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4654G>A	p.Glu1552Lys	missense_variant	Exon 32 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4651G>A	p.Glu1551Lys	missense_variant	Exon 33 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4165G>A	p.Glu1389Lys	missense_variant	Exon 30 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3394G>A	p.Glu1132Lys	missense_variant	Exon 26 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3376G>A	p.Glu1126Lys	missense_variant	Exon 25 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3238G>A	p.Glu1080Lys	missense_variant	Exon 25 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3004G>A	p.Glu1002Lys	missense_variant	Exon 23 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.808G>A	p.Glu270Lys	missense_variant	Exon 6 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248502 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461606 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Aug 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1614 of the SMARCA4 protein (p.Glu1614Lys). This variant is present in population databases (rs768899897, gnomAD 0.006%). 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: 408629). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. 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. -

not provided Uncertain:1

Apr 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function -

Hereditary cancer-predisposing syndrome Benign:1

Aug 04, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	0.015
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.69	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;N;N;.;.;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.23	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;T;T;.;.;.;.
Sift4G	Benign	0.52	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.45	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.;.;.
Vest4		0.44
MutPred		0.17		.;.;Gain of ubiquitination at E1614 (P = 0.0128);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of ubiquitination at E1614 (P = 0.0128);.;.;.;.;
MVP		0.74
MPC		1.1
ClinPred		0.29	T
GERP RS		3.3
Varity_R		0.19
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs768899897; hg19: chr19-11170537; COSMIC: COSV99065447; COSMIC: COSV99065447;