Genetic Variant NM_080650.4:c.362A>T (chr15-35454771-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_080650.4(DPH6):c.362A>T(p.Tyr121Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DPH6
NM_080650.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.72

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPH6	NM_080650.4 link	c.362A>T	p.Tyr121Phe	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.362A>T	p.Tyr121Phe	missense_variant	Exon 4 of 9	1	NM_080650.4	ENSP00000256538.4	Q7L8W6-1
DPH6	ENST00000561411.1 link	c.218A>T	p.Tyr73Phe	missense_variant	Exon 3 of 6	4		ENSP00000453967.1	H0YND7
DPH6	ENST00000559784.5 link	n.323A>T		non_coding_transcript_exon_variant	Exon 3 of 5	3
DPH6	ENST00000558266.5 link	c.-11A>T		upstream_gene_variant		5		ENSP00000454015.1	H0YNH5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457482

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724712

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.71

MutPred

0.92

Loss of sheet (P = 0.1158);.;

MVP

0.74

MPC

0.58

ClinPred

1.0

GERP RS

4.9

Varity_R

0.87

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over