12-50086186-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP6_ModerateBS2

The NM_003076.5(SMARCD1):​c.203G>A​(p.Arg68Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000492 in 1,424,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

SMARCD1
NM_003076.5 missense

Scores

12
7

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.88
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a modified_residue Asymmetric dimethylarginine (size 0) in uniprot entity SMRD1_HUMAN
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.
BP6
Variant 12-50086186-G-A is Benign according to our data. Variant chr12-50086186-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1805271.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMARCD1NM_003076.5 linkuse as main transcriptc.203G>A p.Arg68Gln missense_variant 2/13 ENST00000394963.9 NP_003067.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMARCD1ENST00000394963.9 linkuse as main transcriptc.203G>A p.Arg68Gln missense_variant 2/131 NM_003076.5 ENSP00000378414 P1Q96GM5-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000492
AC:
7
AN:
1424020
Hom.:
0
Cov.:
31
AF XY:
0.00000568
AC XY:
4
AN XY:
704592
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:
0.00000642
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000936
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Coffin-Siris syndrome 11 Benign:1
Likely benign, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMar 31, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0904 - Non-segregation of this variant with the phenotype under investigation has been clearly demonstrated. This variant is heterozygous in the proband’s father who is not known to be affected. (SB) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.052
T;.;T;.;T
Eigen
Uncertain
0.21
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.91
D;D;D;D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Uncertain
0.60
D;D;D;D;D
MetaSVM
Uncertain
0.26
D
MutationAssessor
Benign
1.5
L;L;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-0.18
N;N;N;N;N
REVEL
Uncertain
0.32
Sift
Benign
0.079
T;T;D;D;D
Sift4G
Benign
0.40
T;T;T;T;T
Polyphen
0.98
D;B;.;.;.
Vest4
0.59
MutPred
0.48
Loss of methylation at R68 (P = 0.016);Loss of methylation at R68 (P = 0.016);Loss of methylation at R68 (P = 0.016);Loss of methylation at R68 (P = 0.016);.;
MVP
0.75
MPC
1.2
ClinPred
0.94
D
GERP RS
4.2
Varity_R
0.17
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs764685953; hg19: chr12-50479969; API