19-10984364-G-C

Position:

• chr19-10984364-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001387283.1(SMARCA4):​c.213G>C​(p.Gln71His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,590 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0180

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22238925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.213G>C	p.Gln71His	missense_variant	2/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.213G>C	p.Gln71His	missense_variant	2/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.213G>C	p.Gln71His	missense_variant	2/36		NM_001387283.1	ENSP00000495368
SMARCA4	ENST00000344626.10	c.213G>C	p.Gln71His	missense_variant	2/35	1	NM_003072.5	ENSP00000343896	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434590 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 711260

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 06, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 470288). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 71 of the SMARCA4 protein (p.Gln71His). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The p.Q71H variant (also known as c.213G>C), located in coding exon 1 of the SMARCA4 gene, results from a G to C substitution at nucleotide position 213. The glutamine at codon 71 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.90	L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.
MutationTaster	Benign	0.60	N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.77	N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.013	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G	Benign	0.24	T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T
Polyphen		0.68	P;.;B;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;B
Vest4		0.44
MutPred		0.13		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.65
MPC		0.71
ClinPred		0.67	D
GERP RS		0.087
Varity_R		0.048
gMVP		0.21

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: rs1489673789; hg19: chr19-11095040;