Genetic Variant NM_194249.3:c.470C>T (chr5-140672579-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_194249.3(DND1):c.470C>T(p.Ala157Val) variant causes a missense change. The variant allele was found at a frequency of 0.000144 in 1,577,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

DND1
NM_194249.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.73

Variant links:

Genes affected

DND1 (HGNC:23799): (DND microRNA-mediated repression inhibitor 1) This gene encodes a protein that binds to microRNA-targeting sequences of mRNAs, inhibiting microRNA-mediated repression. Reduced expression of this gene has been implicated in tongue squamous cell carcinoma. Two pseudogenes of this gene are located on the long arm of chromosome 17. [provided by RefSeq, Dec 2010]

DND1 links:

WDR55 (HGNC:25971): (WD repeat domain 55) Predicted to be involved in rRNA processing. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

WDR55 links:

Genome browser will be placed here

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=0.009754658).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DND1	NM_194249.3 link	c.470C>T	p.Ala157Val	missense_variant	Exon 3 of 4	ENST00000542735.2	NP_919225.1	Q8IYX4
WDR55	NM_017706.5 link	c.*2925G>A		downstream_gene_variant		ENST00000358337.10	NP_060176.3	Q9H6Y2-1
WDR55	XM_005268469.4 link	c.*1347G>A		downstream_gene_variant			XP_005268526.1	Q9H6Y2-1
WDR55	XM_017009600.3 link	c.*2925G>A		downstream_gene_variant			XP_016865089.1	G3V1J0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DND1	ENST00000542735.2 link	c.470C>T	p.Ala157Val	missense_variant	Exon 3 of 4	1	NM_194249.3	ENSP00000445366.1		Q8IYX4
WDR55	ENST00000358337.10 link	c.*2925G>A		downstream_gene_variant		1	NM_017706.5	ENSP00000351100.5		Q9H6Y2-1

Frequencies

GnomAD3 genomes

AF:

0.000829

AC:

126

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

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:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000185

AC:

AN:

184108

Hom.:

AF XY:

0.000185

AC XY:

AN XY:

102790

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.000301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000366

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000128

Gnomad OTH exome

AF:

0.000205

GnomAD4 exome

AF:

0.0000701

AC:

100

AN:

1425668

Hom.:

Cov.:

AF XY:

0.0000438

AC XY:

AN XY:

707780

show subpopulations

Gnomad4 AFR exome

AF:

0.00207

Gnomad4 AMR exome

AF:

0.000411

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000477

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.09e-7

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.000834

AC:

127

AN:

152190

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00272

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000175

Hom.:

Bravo

AF:

0.00103

ExAC

AF:

0.000224

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.470C>T (p.A157V) alteration is located in exon 3 (coding exon 3) of the DND1 gene. This alteration results from a C to T substitution at nucleotide position 470, causing the alanine (A) at amino acid position 157 to be replaced by a valine (V). 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

0.096

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.12

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.72

M_CAP

Benign

0.030

MetaRNN

Benign

0.0098

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.80

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.30

REVEL

Benign

0.066

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.085

Vest4

0.21

MutPred

0.42

Loss of disorder (P = 0.0881);

MVP

0.35

MPC

0.77

ClinPred

0.013

GERP RS

5.0

Varity_R

0.16

gMVP

0.42

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