19-10986498-C-G

Variant names:

• chr19-10986498-C-G
• rs533671711
• NM_001387283.1:c.665C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001387283.1(SMARCA4):​c.665C>G​(p.Pro222Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,395,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P222L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.75
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34116098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.665C>G	p.Pro222Arg	missense_variant	Exon 4 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.665C>G	p.Pro222Arg	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.665C>G	p.Pro222Arg	missense_variant	Exon 4 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.665C>G	p.Pro222Arg	missense_variant	Exon 4 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.665C>G	p.Pro222Arg	missense_variant	Exon 4 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.665C>G	p.Pro222Arg	missense_variant	Exon 5 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.665C>G	p.Pro222Arg	missense_variant	Exon 4 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.665C>G	p.Pro222Arg	missense_variant	Exon 4 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.665C>G	p.Pro222Arg	missense_variant	Exon 5 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.77C>G	p.Pro26Arg	missense_variant	Exon 1 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1395742 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 688740

African (AFR) AF: 0.00 AC: 0 AN: 31658

American (AMR) AF: 0.00 AC: 0 AN: 35780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00 AC: 0 AN: 35800

South Asian (SAS) AF: 0.00 AC: 0 AN: 79328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079620

Other (OTH) AF: 0.00 AC: 0 AN: 58016

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.6	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.
PhyloP100		5.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.014	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
Sift4G	Uncertain	0.058	T;.;.;.;.;.;.;.;.;.;T;.;T;D;D;T;D;T
Polyphen		0.43	B;.;D;.;.;.;.;.;.;.;B;.;.;.;.;.;.;D
Vest4		0.58
MutPred		0.25		Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);Loss of glycosylation at P222 (P = 0.0071);
MVP		0.60
MPC		0.52
ClinPred		0.81	D
GERP RS		5.0
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.13
gMVP		0.47
Mutation Taster		=23/77	disease causing

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

Other links and lift over

dbSNP: rs533671711; hg19: chr19-11097174;