chr12-50085511-C-G

Position:

• chr12-50085511-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

The NM_003076.5(SMARCD1):​c.142C>G​(p.Leu48Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,237,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: SMARCD1 NM_003076.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.02

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 Benign. Variant got -8 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=0.018724471).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000659 (10/151820) while in subpopulation SAS AF= 0.000415 (2/4822). AF 95% confidence interval is 0.000073. There are 0 homozygotes in gnomad4. There are 8 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 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCD1	NM_003076.5	c.142C>G	p.Leu48Val	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	c.142C>G	p.Leu48Val	missense_variant	1/13	1	NM_003076.5	ENSP00000378414	P1

Frequencies

GnomAD3 genomes AF: 0.0000659 AC: 10 AN: 151712 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000727 AC: 79 AN: 1086022 Hom.: 0 Cov.: 32 AF XY: 0.0000740 AC XY: 38 AN XY: 513638

Gnomad4 AFR exome AF: 0.0000432

Gnomad4 AMR exome AF: 0.000110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000352

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000618

Gnomad4 OTH exome AF: 0.000160

GnomAD4 genome AF: 0.0000659 AC: 10 AN: 151820 Hom.: 0 Cov.: 30 AF XY: 0.000108 AC XY: 8 AN XY: 74210

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000884

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000718

ExAC AF: 0.0000456 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.142C>G (p.L48V) alteration is located in exon 1 (coding exon 1) of the SMARCD1 gene. This alteration results from a C to G substitution at nucleotide position 142, causing the leucine (L) at amino acid position 48 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Coffin-Siris syndrome 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Mar 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.053	T;.;T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.69	N;N;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.13	N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.55	T;T;T;T
Sift4G	Benign	0.51	T;T;T;T
Polyphen		0.0010	B;D;.;.
Vest4		0.30
MutPred		0.31		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.45
MPC		1.1
ClinPred		0.24	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.14

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: rs548902421; hg19: chr12-50479294;