NM_001282874.2:c.3084G>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 publications found

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]

SMARCA1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics
• X-linked intellectual disability

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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=0.31709152).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282874.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA1	NM_001282874.2	MANE Select	c.3084G>A	p.Met1028Ile	missense	Exon 24 of 25	NP_001269803.1	B7ZLQ5
	SMARCA1	NM_001282875.2		c.3048G>A	p.Met1016Ile	missense	Exon 23 of 24	NP_001269804.1	A0A0A0MRP6
	SMARCA1	NM_003069.5		c.3084G>A	p.Met1028Ile	missense	Exon 24 of 25	NP_003060.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA1	ENST00000371121.5	TSL:1 MANE Select	c.3084G>A	p.Met1028Ile	missense	Exon 24 of 25	ENSP00000360162.4	B7ZLQ5
	SMARCA1	ENST00000371123.5	TSL:1	c.3048G>A	p.Met1016Ile	missense	Exon 23 of 24	ENSP00000360164.2	A0A0A0MRP6
	SMARCA1	ENST00000371122.8	TSL:1	c.3084G>A	p.Met1028Ile	missense	Exon 24 of 25	ENSP00000360163.4	P28370-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000550 AC: 1 AN: 181893 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26101

American (AMR) AF: 0.00 AC: 0 AN: 35054

Ashkenazi Jewish (ASJ) AF: 0.0000519 AC: 1 AN: 19253

East Asian (EAS) AF: 0.00 AC: 0 AN: 30030

South Asian (SAS) AF: 0.00 AC: 0 AN: 53371

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40387

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4095

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 828141

Other (OTH) AF: 0.00 AC: 0 AN: 45517

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Benign	0.41	N
PhyloP100		5.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.30
Sift	Benign	0.21	T
Sift4G	Benign	0.20	T
Polyphen		0.059	B
Vest4		0.37
MutPred		0.47		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
Mutation Taster		=95/5	polymorphism

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: rs147306232; hg19: chrX-128582367;