Genetic Variant DPH7:p.Gly421Ser (chr9-137555337-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138778.5(DPH7):c.1261G>A(p.Gly421Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DPH7
NM_138778.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.304

Variant links:

Genes affected

DPH7 (HGNC:25199): (diphthamide biosynthesis 7) Diphthamide is a post-translationally modified histidine residue present in elongation factor 2, and is the target of diphtheria toxin. This gene encodes a protein that contains a WD-40 domain, and is thought to be involved in diphthamide biosynthesis. A similar protein in yeast functions as a methylesterase, converting methylated diphthine to diphthine, which can then undergo amidation to produce diphthamide. [provided by RefSeq, Oct 2016]

DPH7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04334092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPH7	NM_138778.5 link	c.1261G>A	p.Gly421Ser	missense_variant	Exon 9 of 9	ENST00000277540.7	NP_620133.1	Q9BTV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DPH7	ENST00000277540.7 link	c.1261G>A	p.Gly421Ser	missense_variant	Exon 9 of 9	1	NM_138778.5	ENSP00000277540.2	Q9BTV6
DPH7	ENST00000467243.5 link	n.878G>A		non_coding_transcript_exon_variant	Exon 2 of 2	1
DPH7	ENST00000479650.5 link	n.1364G>A		non_coding_transcript_exon_variant	Exon 7 of 7	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251304

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1261G>A (p.G421S) alteration is located in exon 9 (coding exon 9) of the DPH7 gene. This alteration results from a G to A substitution at nucleotide position 1261, causing the glycine (G) at amino acid position 421 to be replaced by a serine (S). 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

0.072

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

5.8

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.030

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.54

M_CAP

Benign

0.024

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

0.30

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.14

REVEL

Benign

0.054

Sift

Benign

0.89

Sift4G

Benign

0.48

Polyphen

0.0010

Vest4

0.045

MutPred

0.24

Gain of disorder (P = 0.0762);

MVP

0.12

MPC

0.11

ClinPred

0.024

GERP RS

0.88

Varity_R

0.030

gMVP

0.23

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over