12-50085517-C-G

Position:

• chr12-50085517-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4 BS1_Supporting BS2

The NM_003076.5(SMARCD1):​c.148C>G​(p.Arg50Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000566 in 1,236,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: SMARCD1 NM_003076.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63

Genes affected

SMARCD1 (HGNC:11106): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 1) The protein encoded by this gene is a member of the SWI/SNF family of proteins, whose members display helicase and ATPase activities and which 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 and has sequence similarity to the yeast Swp73 protein. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMARCD1
• BP4: Computational evidence support a benign effect (MetaRNN=0.38416055).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000033 (5/151596) while in subpopulation AMR AF= 0.000328 (5/15250). AF 95% confidence interval is 0.000129. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCD1	NM_003076.5	c.148C>G	p.Arg50Gly	missense_variant	1/13	ENST00000394963.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCD1	ENST00000394963.9	c.148C>G	p.Arg50Gly	missense_variant	1/13	1	NM_003076.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151596 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1085164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 513072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000108

Gnomad4 OTH exome AF: 0.0000228

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151596 Hom.: 0 Cov.: 30 AF XY: 0.0000270 AC XY: 2 AN XY: 74002

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.148C>G (p.R50G) alteration is located in coding exon 1 of the SMARCD1 gene. This alteration results from a C to G substitution at nucleotide position 148, causing the arginine (R) at amino acid position 50 to be replaced by a glycine (G). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.148C>G alteration was observed in 0.0032% (1/31020) of total alleles studied. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R50 amino acid is conserved in available vertebrate species. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.R50G alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Benign	0.86
DEOGEN2	Benign	0.059	T;.;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.61	N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.044	D;D;D;D
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.47	P;B;.;.
Vest4		0.47
MutPred		0.30		Loss of methylation at R50 (P = 0.0159);Loss of methylation at R50 (P = 0.0159);Loss of methylation at R50 (P = 0.0159);Loss of methylation at R50 (P = 0.0159);
MVP		0.65
MPC		1.5
ClinPred		0.59	D
GERP RS		3.8
Varity_R		0.27
gMVP		0.37

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: rs954124678; hg19: chr12-50479300;