11-117428440-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_020693.4(DSCAML1):c.6050A>G(p.His2017Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DSCAML1 NM_020693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DSCAML1
• BP4: Computational evidence support a benign effect (MetaRNN=0.15894598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSCAML1	NM_020693.4	c.6050A>G	p.His2017Arg	missense_variant	33/33	ENST00000651296.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSCAML1	ENST00000651296.2	c.6050A>G	p.His2017Arg	missense_variant	33/33		NM_020693.4
DSCAML1	ENST00000321322.6	c.6230A>G	p.His2077Arg	missense_variant	33/33	1		P1
DSCAML1	ENST00000651172.1	c.6230A>G	p.His2077Arg	missense_variant	33/33			P1
DSCAML1	ENST00000527706.5	c.5420A>G	p.His1807Arg	missense_variant	31/31	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000521 AC: 1 AN: 192006 Hom.: 0 AF XY: 0.00000953 AC XY: 1 AN XY: 104924

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: 0.0000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1389240 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 685464

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Jan 02, 2023

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 0.001%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2077 of the DSCAML1 protein (p.His2077Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	21
Dann	Benign	0.95
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.79	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.086
Sift	Benign	0.17	T;T
Sift4G	Benign	0.24	T;T
Vest4		0.31
MVP		0.57
MPC		0.0088
ClinPred		0.19	T
GERP RS		4.8
gMVP		0.30

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: rs1288543114; hg19: chr11-117299156;