Variant 8-2942585-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033225.6(CSMD1):c.10422A>T(p.Gln3474His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CSMD1
NM_033225.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.381

Variant links:

Genes affected

CSMD1 (HGNC:14026): (CUB and Sushi multiple domains 1) Predicted to act upstream of or within several processes, including learning or memory; mammary gland branching involved in pregnancy; and reproductive structure development. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CSMD1 links:

LOC105377785 (HGNC:):

LOC105377785 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06353217).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSMD1	NM_033225.6 linkuse as main transcript	c.10422A>T	p.Gln3474His	missense_variant	69/70	ENST00000635120.2	NP_150094.5	Q96PZ7-1Q59FF8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSMD1	ENST00000635120.2 linkuse as main transcript	c.10422A>T	p.Gln3474His	missense_variant	69/70	5	NM_033225.6	ENSP00000489225.1		Q96PZ7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000467

AC:

AN:

214018

Hom.:

AF XY:

0.00

AC XY:

AN XY:

115026

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442416

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715516

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:

9.08e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The c.10422A>T (p.Q3474H) alteration is located in exon 69 (coding exon 69) of the CSMD1 gene. This alteration results from a A to T substitution at nucleotide position 10422, causing the glutamine (Q) at amino acid position 3474 to be replaced by a histidine (H). 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

0.093

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

5.2

DANN

Benign

0.73

DEOGEN2

Benign

0.021

T;.;.;.;T;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.79

T;.;T;T;.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.064

T;T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.4

.;N;.;.;N;.

REVEL

Benign

0.033

Sift

Uncertain

0.014

.;D;.;.;T;.

Sift4G

Uncertain

0.035

D;D;D;D;D;D

Polyphen

0.0

.;.;.;.;B;B

Vest4

0.14, 0.15, 0.11, 0.12, 0.10

MutPred

0.092

.;.;.;.;Gain of catalytic residue at D3476 (P = 0.0891);Gain of catalytic residue at D3476 (P = 0.0891);

MVP

0.24

ClinPred

0.047

GERP RS

-1.6

Varity_R

0.069

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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