X-129448390-C-T

Variant names:

• chrX-129448390-C-T
• rs147306232
• NM_001282874.2:c.3084G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001282874.2(SMARCA1):​c.3084G>A​(p.Met1028Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000924 in 1,081,949 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1028V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: SMARCA1 NM_001282874.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.33

Genes affected

SMARCA1 (HGNC:11097): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 1) This gene encodes a member of the SWI/SNF family of proteins. The encoded protein is an ATPase which is expressed in diverse tissues and contributes to the chromatin remodeling complex that is involved in transcription. The protein may also play a role in DNA damage, growth inhibition and apoptosis of cancer cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31709152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA1	NM_001282874.2	c.3084G>A	p.Met1028Ile	missense_variant	Exon 24 of 25	ENST00000371121.5	NP_001269803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA1	ENST00000371121.5	c.3084G>A	p.Met1028Ile	missense_variant	Exon 24 of 25	1	NM_001282874.2	ENSP00000360162.4
SMARCA1	ENST00000371123.5	c.3048G>A	p.Met1016Ile	missense_variant	Exon 23 of 24	1		ENSP00000360164.2
SMARCA1	ENST00000371122.8	c.3084G>A	p.Met1028Ile	missense_variant	Exon 24 of 25	1		ENSP00000360163.4
SMARCA1	ENST00000617310.4	n.3402G>A		non_coding_transcript_exon_variant	Exon 22 of 23	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000550 AC: 1 AN: 181893 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66549

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1081949 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 348631

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000519

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.063	T;T;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Benign	0.41	N;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.21	T;T;.
Sift4G	Benign	0.20	T;T;T
Polyphen		0.059	B;.;B
Vest4		0.37
MutPred		0.47		Loss of disorder (P = 0.199);.;Loss of disorder (P = 0.199);
MVP		0.78
MPC		0.73
ClinPred		0.30	T
GERP RS		5.9
Varity_R		0.58
gMVP		0.40

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: rs147306232; hg19: chrX-128582367;