Genetic Variant NM_080650.4:c.368G>A (chr15-35454765-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_080650.4(DPH6):c.368G>A(p.Arg123His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00066 in 1,608,776 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00068 ( 1 hom. )

Consequence

DPH6
NM_080650.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93

Variant links:

Genes affected

DPH6 (HGNC:30543): (diphthamine biosynthesis 6) Enables diphthine-ammonia ligase activity. Predicted to be involved in peptidyl-diphthamide biosynthetic process from peptidyl-histidine. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DPH6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35365966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPH6	NM_080650.4 link	c.368G>A	p.Arg123His	missense_variant	Exon 4 of 9	ENST00000256538.9	NP_542381.1	Q7L8W6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DPH6	ENST00000256538.9 link	c.368G>A	p.Arg123His	missense_variant	Exon 4 of 9	1	NM_080650.4	ENSP00000256538.4	Q7L8W6-1
DPH6	ENST00000561411.1 link	c.224G>A	p.Arg75His	missense_variant	Exon 3 of 6	4		ENSP00000453967.1	H0YND7
DPH6	ENST00000559784.5 link	n.329G>A		non_coding_transcript_exon_variant	Exon 3 of 5	3
DPH6	ENST00000558266.5 link	c.-5G>A		upstream_gene_variant		5		ENSP00000454015.1	H0YNH5

Frequencies

GnomAD3 genomes

AF:

0.000500

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000445

AC:

110

AN:

247350

Hom.:

AF XY:

0.000448

AC XY:

AN XY:

133790

show subpopulations

Gnomad AFR exome

AF:

0.0000624

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000135

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.000871

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000676

AC:

985

AN:

1456632

Hom.:

Cov.:

AF XY:

0.000663

AC XY:

480

AN XY:

724332

show subpopulations

Gnomad4 AFR exome

AF:

0.0000902

Gnomad4 AMR exome

AF:

0.0000910

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000118

Gnomad4 FIN exome

AF:

0.000244

Gnomad4 NFE exome

AF:

0.000832

Gnomad4 OTH exome

AF:

0.000482

GnomAD4 genome

AF:

0.000500

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.00104

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000887

Hom.:

Bravo

AF:

0.000408

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000700

AC:

ExAC

AF:

0.000412

AC:

EpiCase

AF:

0.000714

EpiControl

AF:

0.000778

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.368G>A (p.R123H) alteration is located in exon 4 (coding exon 4) of the DPH6 gene. This alteration results from a G to A substitution at nucleotide position 368, causing the arginine (R) at amino acid position 123 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

T;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.35

T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Pathogenic

4.0

H;.

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

D;.

Vest4

0.34

MVP

0.73

MPC

0.24

ClinPred

0.65

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.86

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