chr8-112224816-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

CSMD3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198123.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSMD3	NM_198123.2	MANE Select	c.11079G>A	p.Ala3693Ala	synonymous	Exon 71 of 71	NP_937756.1	Q7Z407-1
	CSMD3	NM_198124.2		c.10959G>A	p.Ala3653Ala	synonymous	Exon 72 of 72	NP_937757.1	Q7Z407-2
	CSMD3	NM_052900.3		c.10572G>A	p.Ala3524Ala	synonymous	Exon 69 of 69	NP_443132.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSMD3	ENST00000297405.10	TSL:1 MANE Select	c.11079G>A	p.Ala3693Ala	synonymous	Exon 71 of 71	ENSP00000297405.5	Q7Z407-1
	CSMD3	ENST00000343508.7	TSL:1	c.10959G>A	p.Ala3653Ala	synonymous	Exon 72 of 72	ENSP00000345799.3	Q7Z407-2
	CSMD3	ENST00000455883.2	TSL:1	c.10572G>A	p.Ala3524Ala	synonymous	Exon 69 of 69	ENSP00000412263.2	Q7Z407-3

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

GnomAD2 exomes AF: 0.0971 AC: 24414 AN: 251424 AF XY: 0.0999

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 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

African (AFR) AF: 0.0206 AC: 689 AN: 33478

American (AMR) AF: 0.0673 AC: 3010 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 4019 AN: 26132

East Asian (EAS) AF: 0.00186 AC: 74 AN: 39692

South Asian (SAS) AF: 0.0765 AC: 6602 AN: 86256

European-Finnish (FIN) AF: 0.153 AC: 8158 AN: 53418

Middle Eastern (MID) AF: 0.191 AC: 1102 AN: 5768

European-Non Finnish (NFE) AF: 0.118 AC: 131330 AN: 1111660

Other (OTH) AF: 0.112 AC: 6778 AN: 60380

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

African (AFR) AF: 0.0205 AC: 851 AN: 41520

American (AMR) AF: 0.0841 AC: 1285 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 515 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5170

South Asian (SAS) AF: 0.0659 AC: 318 AN: 4828

European-Finnish (FIN) AF: 0.160 AC: 1691 AN: 10580

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8161 AN: 68000

Other (OTH) AF: 0.104 AC: 219 AN: 2108

Alfa AF: 0.115 Hom.: 2421

Bravo AF: 0.0787

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.135

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CSMD3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.3
DANN	Benign	0.67
PhyloP100		-2.7
Mutation Taster		=86/14	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4876458; hg19: chr8-113237045; COSMIC: COSV52183531;