15-35450686-C-G

Variant names:

• chr15-35450686-C-G
• rs565863034
• NM_080650.4:c.504G>C
• DPH6 p.Leu168Phe

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.504G>C​(p.Leu168Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPH6 NM_080650.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001143
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0810
• 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=0.21195754).

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.504G>C	p.Leu168Phe	missense splice_region	Exon 5 of 9	NP_542381.1	Q7L8W6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH6	ENST00000256538.9	TSL:1 MANE Select	c.504G>C	p.Leu168Phe	missense splice_region	Exon 5 of 9	ENSP00000256538.4	Q7L8W6-1
	DPH6	ENST00000896513.1		c.504G>C	p.Leu168Phe	missense splice_region	Exon 5 of 9	ENSP00000566572.1
	DPH6	ENST00000561411.1	TSL:4	c.360G>C	p.Leu120Phe	missense splice_region	Exon 4 of 6	ENSP00000453967.1	H0YND7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0063	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.070	N
PhyloP100		-0.081
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.053
Sift	Benign	0.19	T
Sift4G	Benign	0.30	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0040
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs565863034;

hg19: chr15-35742887;