chr21-40013118-C-T

Position:

chr21-40013118-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_001389.5(DSCAM):c.5955G>A(p.Met1985Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000646 in 1,609,616 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

DSCAM
NM_001389.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.07

Variant links:

Genes affected

DSCAM (HGNC:3039): (DS cell adhesion molecule) This gene is a member of the immunoglobulin superfamily of cell adhesion molecules (Ig-CAMs), and is involved in human central and peripheral nervous system development. This gene is a candidate for Down syndrome and congenital heart disease (DSCHD). A gene encoding a similar Ig-CAM protein is located on chromosome 11. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2012]

DSCAM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DSCAM. . Gene score misZ 3.2228 (greater than the threshold 3.09). Trascript score misZ 4.4297 (greater than threshold 3.09). GenCC has associacion of gene with autism spectrum disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.021125525).

BS2

High AC in GnomAd4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSCAM	NM_001389.5 linkuse as main transcript	c.5955G>A	p.Met1985Ile	missense_variant	33/33	ENST00000400454.6	NP_001380.2
DSCAM	NM_001271534.3 linkuse as main transcript	c.5901G>A	p.Met1967Ile	missense_variant	33/33		NP_001258463.1
DSCAM	XM_017028281.2 linkuse as main transcript	c.5247G>A	p.Met1749Ile	missense_variant	30/30		XP_016883770.1
DSCAM	NR_073202.3 linkuse as main transcript	n.6261G>A		non_coding_transcript_exon_variant	33/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSCAM	ENST00000400454.6 linkuse as main transcript	c.5955G>A	p.Met1985Ile	missense_variant	33/33	1	NM_001389.5	ENSP00000383303	P1	O60469-1
DSCAM	ENST00000404019.2 linkuse as main transcript	c.5157G>A	p.Met1719Ile	missense_variant	29/29	1		ENSP00000385342
DSCAM	ENST00000617870.4 linkuse as main transcript	c.5460G>A	p.Met1820Ile	missense_variant	30/30	5		ENSP00000478698

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000526

AC:

AN:

247148

Hom.:

AF XY:

0.0000671

AC XY:

AN XY:

134046

show subpopulations

Gnomad AFR exome

AF:

0.000842

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000309

AC:

AN:

1457398

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

724362

show subpopulations

Gnomad4 AFR exome

AF:

0.00126

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:

0.00

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.000388

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000547

Hom.:

Bravo

AF:

0.000408

ESP6500AA

AF:

0.000514

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000662

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.5955G>A (p.M1985I) alteration is located in exon 33 (coding exon 33) of the DSCAM gene. This alteration results from a G to A substitution at nucleotide position 5955, causing the methionine (M) at amino acid position 1985 to be replaced by an isoleucine (I). 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

0.24

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.053

T;.;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.014

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.0052

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.41

N;.;.

MutationTaster

Benign

0.80

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.2

N;.;N

REVEL

Benign

0.080

Sift

Benign

0.13

T;.;T

Sift4G

Benign

0.56

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.15

MutPred

0.15

Gain of glycosylation at S1988 (P = 0.082);.;.;

MVP

0.36

MPC

0.59

ClinPred

0.087

GERP RS

4.5

Varity_R

0.31

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

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