rs1060504456

Variant names:

• chr19-11061807-A-C
• rs1060504456
• NM_001387283.1:c.5031A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-11061807-A-C
• chr19-11061807-A-G

Variant summary

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

The NM_003072.5(SMARCA4):​c.4935A>C​(p.Glu1645Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.841

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 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=0.088979036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.5031A>C	p.Glu1677Asp	missense_variant	Exon 36 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4935A>C	p.Glu1645Asp	missense_variant	Exon 35 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.5031A>C	p.Glu1677Asp	missense_variant	Exon 36 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4935A>C	p.Glu1645Asp	missense_variant	Exon 35 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4941A>C	p.Glu1647Asp	missense_variant	Exon 35 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4845A>C	p.Glu1615Asp	missense_variant	Exon 35 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4845A>C	p.Glu1615Asp	missense_variant	Exon 34 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4845A>C	p.Glu1615Asp	missense_variant	Exon 34 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4842A>C	p.Glu1614Asp	missense_variant	Exon 35 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4356A>C	p.Glu1452Asp	missense_variant	Exon 32 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3585A>C	p.Glu1195Asp	missense_variant	Exon 28 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3567A>C	p.Glu1189Asp	missense_variant	Exon 27 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3429A>C	p.Glu1143Asp	missense_variant	Exon 27 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3195A>C	p.Glu1065Asp	missense_variant	Exon 25 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.999A>C	p.Glu333Asp	missense_variant	Exon 8 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

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: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.089	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-0.81	N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.080	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.28	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.
Sift4G	Benign	0.85	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.
Polyphen		0.72	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.;.
Vest4		0.30
MutPred		0.079		.;.;Gain of glycosylation at S1674 (P = 0.1399);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of glycosylation at S1674 (P = 0.1399);.;.;.;
MVP		0.67
MPC		0.89
ClinPred		0.39	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.039
gMVP		0.34

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: rs1060504456; hg19: chr19-11172483;