15-35538464-C-A

Variant names:

• chr15-35538464-C-A
• rs34907758
• NM_080650.4:c.122G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080650.4(DPH6):​c.122G>T​(p.Gly41Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,360,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G41E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: DPH6 NM_080650.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0130
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.086768836).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080650.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH6	NM_080650.4	MANE Select	c.122G>T	p.Gly41Val	missense	Exon 3 of 9	NP_542381.1	Q7L8W6-1
	DPH6	NM_001141972.2		c.122G>T	p.Gly41Val	missense	Exon 3 of 4	NP_001135444.1	Q7L8W6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH6	ENST00000256538.9	TSL:1 MANE Select	c.122G>T	p.Gly41Val	missense	Exon 3 of 9	ENSP00000256538.4	Q7L8W6-1
	DPH6	ENST00000440392.3	TSL:1	c.122G>T	p.Gly41Val	missense	Exon 3 of 4	ENSP00000406976.2	Q7L8W6-2
	DPH6	ENST00000896513.1		c.122G>T	p.Gly41Val	missense	Exon 3 of 9	ENSP00000566572.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1360486 Hom.: 0 Cov.: 30 AF XY: 0.00000150 AC XY: 1 AN XY: 667610

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31524

American (AMR) AF: 0.00 AC: 0 AN: 39040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23494

East Asian (EAS) AF: 0.00 AC: 0 AN: 37896

South Asian (SAS) AF: 0.00 AC: 0 AN: 71314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5378

European-Non Finnish (NFE) AF: 9.55e-7 AC: 1 AN: 1046768

Other (OTH) AF: 0.0000181 AC: 1 AN: 55182

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	L
PhyloP100		-0.013
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.018
Sift	Benign	0.082	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.44		Gain of helix (P = 0.027)
MVP		0.24
MPC		0.22
ClinPred		0.097	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.39

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

Other links and lift over

dbSNP: rs34907758; hg19: chr15-35830665;