X-129481079-G-T

Position:

• chrX-129481079-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_001282874.2(SMARCA1):​c.2324C>A​(p.Pro775Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,177,363 control chromosomes in the GnomAD database, including 4 homozygotes. There are 74 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., 11 hem., cov: 22)
  • Exomes 𝑓: 0.00018 (3 hom. 63 hem.)
• Consequence: SMARCA1 NM_001282874.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.007953227).
• BP6: Variant X-129481079-G-T is Benign according to our data. Variant chrX-129481079-G-T is described in ClinVar as [Benign]. Clinvar id is 722222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA1	NM_001282874.2	c.2324C>A	p.Pro775Gln	missense_variant	18/25	ENST00000371121.5	NP_001269803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA1	ENST00000371121.5	c.2324C>A	p.Pro775Gln	missense_variant	18/25	1	NM_001282874.2	ENSP00000360162.4
SMARCA1	ENST00000371123.5	c.2288C>A	p.Pro763Gln	missense_variant	17/24	1		ENSP00000360164.2
SMARCA1	ENST00000371122.8	c.2324C>A	p.Pro775Gln	missense_variant	18/25	1		ENSP00000360163.4
SMARCA1	ENST00000617310.4	n.2382C>A		non_coding_transcript_exon_variant	17/23	2

Frequencies

GnomAD3 genomes AF: 0.000340 AC: 38 AN: 111888 Hom.: 1 Cov.: 22 AF XY: 0.000323 AC XY: 11 AN XY: 34066

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00866

Gnomad SAS AF: 0.000744

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000618 AC: 108 AN: 174703 Hom.: 1 AF XY: 0.000519 AC XY: 31 AN XY: 59757

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000394

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00738

Gnomad SAS exome AF: 0.000356

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000927

GnomAD4 exome AF: 0.000185 AC: 197 AN: 1065424 Hom.: 3 Cov.: 24 AF XY: 0.000188 AC XY: 63 AN XY: 335626

Gnomad4 AFR exome AF: 0.0000390

Gnomad4 AMR exome AF: 0.0000292

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00304

Gnomad4 SAS exome AF: 0.000344

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000614

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.000339 AC: 38 AN: 111939 Hom.: 1 Cov.: 22 AF XY: 0.000322 AC XY: 11 AN XY: 34127

Gnomad4 AFR AF: 0.0000648

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00868

Gnomad4 SAS AF: 0.000747

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.000498 Hom.: 15

Bravo AF: 0.000366

ExAC AF: 0.000560 AC: 68

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.0080	T;T;T
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.1	D;D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.019	D;D;.
Sift4G	Uncertain	0.018	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.20
MVP		0.88
MPC		1.5
ClinPred		0.12	T
GERP RS		5.8
Varity_R		0.53
gMVP		0.67

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: rs186125032; hg19: chrX-128615056;