15-35450709-T-A

Variant names:

• chr15-35450709-T-A
• rs750653114
• NM_080650.4:c.481A>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.481A>T​(p.Met161Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,990 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. M161I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DPH6 NM_080650.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• Publications: 1 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=0.107996196).

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.481A>T	p.Met161Leu	missense	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.481A>T	p.Met161Leu	missense	Exon 5 of 9	ENSP00000256538.4	Q7L8W6-1
	DPH6	ENST00000896513.1		c.481A>T	p.Met161Leu	missense	Exon 5 of 9	ENSP00000566572.1
	DPH6	ENST00000561411.1	TSL:4	c.337A>T	p.Met113Leu	missense	Exon 4 of 6	ENSP00000453967.1	H0YND7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250684 AF XY: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460990 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726784

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111622

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.69
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.72	N
REVEL	Benign	0.082
Sift	Benign	0.11	T
Sift4G	Benign	0.098	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.66		Gain of ubiquitination at K164 (P = 0.0975)
MVP		0.20
MPC		0.16
ClinPred		0.041	T
GERP RS		-4.0
Varity_R		0.13
gMVP		0.61
Mutation Taster		=94/6	polymorphism

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: rs750653114; hg19: chr15-35742910;