15-35381867-T-C

Position:

• chr15-35381867-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_080650.4(DPH6):​c.617A>G​(p.Glu206Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: DPH6 NM_080650.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

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 (HGNC:):

ACMG classification

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, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPH6	NM_080650.4	c.617A>G	p.Glu206Gly	missense_variant	7/9	ENST00000256538.9	NP_542381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPH6	ENST00000256538.9	c.617A>G	p.Glu206Gly	missense_variant	7/9	1	NM_080650.4	ENSP00000256538.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461478 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727070

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2023

The c.617A>G (p.E206G) alteration is located in exon 7 (coding exon 7) of the DPH6 gene. This alteration results from a A to G substitution at nucleotide position 617, causing the glutamic acid (E) at amino acid position 206 to be replaced by a glycine (G). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;T;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	4.2	H;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.9	D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.95
MutPred		0.93		Loss of catalytic residue at E206 (P = 0.1064);.;.;
MVP		0.68
MPC		0.77
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-35674068;