8-112224816-C-T

Variant names:

• chr8-112224816-C-T
• rs4876458
• NM_198123.2:c.11079G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_198123.2(CSMD3):​c.11079G>A​(p.Ala3693Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,613,672 control chromosomes in the GnomAD database, including 10,379 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.087 (762 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9617 hom.)
• Consequence: CSMD3 NM_198123.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.67

Genes affected

CSMD3 (HGNC:19291): (CUB and Sushi multiple domains 3) Predicted to be involved in regulation of dendrite development. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-112224816-C-T is Benign according to our data. Variant chr8-112224816-C-T is described in ClinVar as [Benign]. Clinvar id is 3056930.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-2.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSMD3	NM_198123.2	c.11079G>A	p.Ala3693Ala	synonymous_variant	Exon 71 of 71	ENST00000297405.10	NP_937756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSMD3	ENST00000297405.10	c.11079G>A	p.Ala3693Ala	synonymous_variant	Exon 71 of 71	1	NM_198123.2	ENSP00000297405.5

Frequencies

GnomAD3 genomes AF: 0.0871 AC: 13248 AN: 152048 Hom.: 761 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0652

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.0971 AC: 24414 AN: 251424 Hom.: 1490 AF XY: 0.0999 AC XY: 13570 AN XY: 135884

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.0663

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.00174

Gnomad SAS exome AF: 0.0760

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.111 AC: 161762 AN: 1461506 Hom.: 9617 Cov.: 32 AF XY: 0.110 AC XY: 79873 AN XY: 727082

Gnomad4 AFR exome AF: 0.0206

Gnomad4 AMR exome AF: 0.0673

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.00186

Gnomad4 SAS exome AF: 0.0765

Gnomad4 FIN exome AF: 0.153

Gnomad4 NFE exome AF: 0.118

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.0870 AC: 13242 AN: 152166 Hom.: 762 Cov.: 32 AF XY: 0.0879 AC XY: 6542 AN XY: 74404

Gnomad4 AFR AF: 0.0205

Gnomad4 AMR AF: 0.0841

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0659

Gnomad4 FIN AF: 0.160

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.104

Alfa AF: 0.117 Hom.: 1894

Bravo AF: 0.0787

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.135

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CSMD3-related disorder Benign:1

Dec 20, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.3
DANN	Benign	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: rs4876458; hg19: chr8-113237045; COSMIC: COSV52183531;