NM_001387283.1:c.3950T>A

Variant names:

• chr19-11034199-T-A
• rs1555785051
• NM_001387283.1:c.3950T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001387283.1(SMARCA4):​c.3950T>A​(p.Met1317Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. M1317I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_001387283.1 missense, splice_region
• Scores: Splicing: ADA: 0.001955
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.73
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3950T>A	p.Met1317Lys	missense_variant, splice_region_variant	Exon 28 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3950T>A	p.Met1317Lys	missense_variant, splice_region_variant	Exon 28 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3950T>A	p.Met1317Lys	missense_variant, splice_region_variant	Exon 28 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3950T>A	p.Met1317Lys	missense_variant, splice_region_variant	Exon 28 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3851T>A	p.Met1284Lys	missense_variant, splice_region_variant	Exon 27 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3851T>A	p.Met1284Lys	missense_variant, splice_region_variant	Exon 28 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3851T>A	p.Met1284Lys	missense_variant, splice_region_variant	Exon 27 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3851T>A	p.Met1284Lys	missense_variant, splice_region_variant	Exon 27 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3851T>A	p.Met1284Lys	missense_variant, splice_region_variant	Exon 28 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3362T>A	p.Met1121Lys	missense_variant, splice_region_variant	Exon 25 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2594T>A	p.Met865Lys	missense_variant, splice_region_variant	Exon 21 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2576T>A	p.Met859Lys	missense_variant, splice_region_variant	Exon 20 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2435T>A	p.Met812Lys	missense_variant, splice_region_variant	Exon 20 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2303T>A	p.Met768Lys	missense_variant, splice_region_variant	Exon 19 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.107T>A	p.Met36Lys	missense_variant, splice_region_variant	Exon 2 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Benign	0.86
DEOGEN2	Benign	0.35	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.099
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.0	N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.94	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;.;.;.;.;.
REVEL	Uncertain	0.53
Sift	Benign	0.25	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.31	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.012	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.84
MutPred		0.47		Gain of ubiquitination at M1317 (P = 0.0045);.;Gain of ubiquitination at M1317 (P = 0.0045);.;.;.;.;.;.;.;Gain of ubiquitination at M1317 (P = 0.0045);.;.;.;.;.;.;Gain of ubiquitination at M1317 (P = 0.0045);.;.;.;.;
MVP		0.94
MPC		2.7
ClinPred		0.77	D
GERP RS		4.6
PromoterAI		0.087	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.65
gMVP		0.93
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0020
dbscSNV1_RF	Benign	0.10
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: rs1555785051; hg19: chr19-11144875;