19-10986198-C-T

Position:

• chr19-10986198-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_003072.5(SMARCA4):​c.365C>T​(p.Ser122Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,462 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.81

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ 6.8459 (greater than the threshold 3.09). Trascript score misZ 8.7957 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.365C>T	p.Ser122Leu	missense_variant	4/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.365C>T	p.Ser122Leu	missense_variant	4/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.365C>T	p.Ser122Leu	missense_variant	4/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.365C>T	p.Ser122Leu	missense_variant	4/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.365C>T	p.Ser122Leu	missense_variant	4/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.365C>T	p.Ser122Leu	missense_variant	5/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.365C>T	p.Ser122Leu	missense_variant	4/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.365C>T	p.Ser122Leu	missense_variant	4/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.365C>T	p.Ser122Leu	missense_variant	5/35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461462 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 122 of the SMARCA4 protein (p.Ser122Leu). 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: 484861). Advanced 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 at Invitae 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2023	- -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16;C5935610:Otosclerosis 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 17, 2024

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2022

The p.S122L variant (also known as c.365C>T), located in coding exon 3 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 365. The serine at codon 122 is replaced by leucine, an amino acid with dissimilar properties. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	0.39
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;.;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.1	L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.8	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G	Benign	0.077	T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T
Polyphen		0.99	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D
Vest4		0.86
MutPred		0.23		Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);Loss of glycosylation at S122 (P = 0.0059);
MVP		0.87
MPC		0.77
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.46
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555752859; hg19: chr19-11096874; COSMIC: COSV60793545; COSMIC: COSV60793545;