NM_001387283.1:c.4925A>C

Variant names:

• chr19-11060105-A-C
• rs1555796263
• NM_001387283.1:c.4925A>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BS1_Supporting BS2

The NM_001387283.1(SMARCA4):​c.4925A>C​(p.Lys1642Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000516 in 1,551,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.25

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 -4 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.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000005 (7/1399514) while in subpopulation EAS AF= 0.000196 (7/35748). AF 95% confidence interval is 0.000091. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4925A>C	p.Lys1642Thr	missense_variant	Exon 35 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4829A>C	p.Lys1610Thr	missense_variant	Exon 34 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4925A>C	p.Lys1642Thr	missense_variant	Exon 35 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4829A>C	p.Lys1610Thr	missense_variant	Exon 34 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4835A>C	p.Lys1612Thr	missense_variant	Exon 34 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4739A>C	p.Lys1580Thr	missense_variant	Exon 34 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4739A>C	p.Lys1580Thr	missense_variant	Exon 33 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4739A>C	p.Lys1580Thr	missense_variant	Exon 33 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4736A>C	p.Lys1579Thr	missense_variant	Exon 34 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4250A>C	p.Lys1417Thr	missense_variant	Exon 31 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3479A>C	p.Lys1160Thr	missense_variant	Exon 27 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3461A>C	p.Lys1154Thr	missense_variant	Exon 26 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3323A>C	p.Lys1108Thr	missense_variant	Exon 26 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3089A>C	p.Lys1030Thr	missense_variant	Exon 24 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.893A>C	p.Lys298Thr	missense_variant	Exon 7 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 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: 0.000192

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

GnomAD4 exome AF: 0.00000500 AC: 7 AN: 1399514 Hom.: 0 Cov.: 33 AF XY: 0.00000435 AC XY: 3 AN XY: 690372

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000196

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

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

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 1642 of the SMARCA4 protein (p.Lys1642Thr). 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: 470425). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K1642T variant (also known as c.4925A>C), located in coding exon 34 of the SMARCA4 gene, results from an A to C substitution at nucleotide position 4925. The lysine at codon 1642 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	0.086
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.3	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.
REVEL	Uncertain	0.42
Sift	Benign	0.062	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.
Sift4G	Uncertain	0.035	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;T;D;.;.;.;.
Polyphen		0.92	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.;.;.
Vest4		0.41
MutPred		0.21		.;.;Gain of phosphorylation at K1642 (P = 0.0028);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of phosphorylation at K1642 (P = 0.0028);.;.;.;.;
MVP		0.69
MPC		1.7
ClinPred		0.82	D
GERP RS		4.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.22
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: rs1555796263; hg19: chr19-11170781;