chr19-10986512-G-T

Variant names:

• chr19-10986512-G-T
• rs769096295
• NM_001387283.1:c.679G>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP6 BS2

The NM_003072.5(SMARCA4):​c.679G>T​(p.Ala227Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,545,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict 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: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.65

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.
• BP6: Variant 19-10986512-G-T is Benign according to our data. Variant chr19-10986512-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408677.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.679G>T	p.Ala227Ser	missense_variant	Exon 4 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.679G>T	p.Ala227Ser	missense_variant	Exon 4 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.679G>T	p.Ala227Ser	missense_variant	Exon 4 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.679G>T	p.Ala227Ser	missense_variant	Exon 4 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.679G>T	p.Ala227Ser	missense_variant	Exon 4 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.679G>T	p.Ala227Ser	missense_variant	Exon 5 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.679G>T	p.Ala227Ser	missense_variant	Exon 4 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.679G>T	p.Ala227Ser	missense_variant	Exon 4 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.679G>T	p.Ala227Ser	missense_variant	Exon 5 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.91G>T	p.Ala31Ser	missense_variant	Exon 1 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000212 AC: 3 AN: 141392 Hom.: 0 AF XY: 0.0000131 AC XY: 1 AN XY: 76510

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000565

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000122 AC: 17 AN: 1392998 Hom.: 0 Cov.: 34 AF XY: 0.0000131 AC XY: 9 AN XY: 687416

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: 0.0000148

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 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

Jun 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 227 of the SMARCA4 protein (p.Ala227Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 408677). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 Benign:1

Nov 16, 2023

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	0.066
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.18	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.0	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.14	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Benign	0.18
Sift	Benign	0.34	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.79	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.0010	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B
Vest4		0.33
MutPred		0.21		Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);Gain of glycosylation at A227 (P = 0.0017);
MVP		0.39
MPC		0.23
ClinPred		0.11	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.030
gMVP		0.056

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs769096295; hg19: chr19-11097188;