NM_001387283.1:c.3127C>G

Variant names:

• chr19-11025467-C-G
• NM_001387283.1:c.3127C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_001387283.1(SMARCA4):​c.3127C>G​(p.Arg1043Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1043W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.449

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11025467-C-T is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3127C>G	p.Arg1043Gly	missense_variant	Exon 22 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3127C>G	p.Arg1043Gly	missense_variant	Exon 22 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3127C>G	p.Arg1043Gly	missense_variant	Exon 22 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3127C>G	p.Arg1043Gly	missense_variant	Exon 22 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3127C>G	p.Arg1043Gly	missense_variant	Exon 22 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3127C>G	p.Arg1043Gly	missense_variant	Exon 23 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3127C>G	p.Arg1043Gly	missense_variant	Exon 22 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3127C>G	p.Arg1043Gly	missense_variant	Exon 22 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3127C>G	p.Arg1043Gly	missense_variant	Exon 23 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2539C>G	p.Arg847Gly	missense_variant	Exon 19 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1771C>G	p.Arg591Gly	missense_variant	Exon 15 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1852C>G	p.Arg618Gly	missense_variant	Exon 15 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1612C>G	p.Arg538Gly	missense_variant	Exon 14 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1480C>G	p.Arg494Gly	missense_variant	Exon 13 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;T;D;.;.;.;.
Eigen	Benign	0.020
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.34	N
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;H;H;.;H;H;H;H;H;H;H;H;H;.;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.94
MutPred		0.79		Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);.;Loss of MoRF binding (P = 0.0382);.;.;.;.;
MVP		0.98
MPC		3.7
ClinPred		1.0	D
GERP RS		-2.3
Varity_R		0.97
gMVP		1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11136143;