12-50085517-C-G

Position:

chr12-50085517-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BS1_SupportingBS2

The ENST00000394963.9(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
ENST00000394963.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.63

Variant links:

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]

SMARCD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCD1. . Gene score misZ 3.4416 (greater than the threshold 3.09). Trascript score misZ 3.2646 (greater than threshold 3.09). GenCC has associacion of gene with Coffin-Siris syndrome 11, autism, susceptibility to, 15, Coffin-Siris syndrome.

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	Protein	UniProt
SMARCD1	NM_003076.5 linkuse as main transcript	c.148C>G	p.Arg50Gly	missense_variant	1/13	ENST00000394963.9	NP_003067.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCD1	ENST00000394963.9 linkuse as main transcript	c.148C>G	p.Arg50Gly	missense_variant	1/13	1	NM_003076.5	ENSP00000378414	P1	Q96GM5-1

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151596

Hom.:

Cov.:

show subpopulations

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:

AN:

1085164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

513072

show subpopulations

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:

AN:

151596

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74002

show subpopulations

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

LINK: link

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

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Benign

0.86

DEOGEN2

Benign

0.059

T;.;T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.38

T;T;T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.8

L;L;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.95

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over