11-117428446-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_020693.4(DSCAML1):c.6044G>A(p.Gly2015Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000195 in 1,385,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: DSCAML1 NM_020693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

Genes affected

DSCAML1 (HGNC:14656): (DS cell adhesion molecule like 1) The protein encoded by this gene is a member of the Ig superfamily of cell adhesion molecules and is involved in neuronal differentiation. The encoded membrane-bound protein localizes to the cell surface, where it forms aggregates that repel neuronal processes of the same cell type. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DSCAML1
• BP4: Computational evidence support a benign effect (MetaRNN=0.15290222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSCAML1	NM_020693.4	c.6044G>A	p.Gly2015Asp	missense_variant	33/33	ENST00000651296.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSCAML1	ENST00000651296.2	c.6044G>A	p.Gly2015Asp	missense_variant	33/33		NM_020693.4
DSCAML1	ENST00000321322.6	c.6224G>A	p.Gly2075Asp	missense_variant	33/33	1		P1
DSCAML1	ENST00000651172.1	c.6224G>A	p.Gly2075Asp	missense_variant	33/33			P1
DSCAML1	ENST00000527706.5	c.5414G>A	p.Gly1805Asp	missense_variant	31/31	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000107 AC: 2 AN: 187314 Hom.: 0 AF XY: 0.0000196 AC XY: 2 AN XY: 102190

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: 0.000108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000195 AC: 27 AN: 1385238 Hom.: 0 Cov.: 33 AF XY: 0.0000132 AC XY: 9 AN XY: 682888

Gnomad4 AFR exome AF: 0.0000330

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000772

Gnomad4 SAS exome AF: 0.000226

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000465

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 20, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with DSCAML1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2075 of the DSCAML1 protein (p.Gly2075Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.73	N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.13	T;T
Vest4		0.28
MVP		0.62
MPC		0.0095
ClinPred		0.20	T
GERP RS		3.9
gMVP		0.18

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: rs916593525; hg19: chr11-117299162;