chr15-35538352-G-C

Variant names:

• chr15-35538352-G-C
• rs748153954
• NM_080650.4:c.234C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_080650.4(DPH6):​c.234C>G​(p.Ser78Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DPH6 NM_080650.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.269
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3377915).

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.234C>G	p.Ser78Arg	missense	Exon 3 of 9	NP_542381.1	Q7L8W6-1
	DPH6	NM_001141972.2		c.234C>G	p.Ser78Arg	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.234C>G	p.Ser78Arg	missense	Exon 3 of 9	ENSP00000256538.4	Q7L8W6-1
	DPH6	ENST00000440392.3	TSL:1	c.234C>G	p.Ser78Arg	missense	Exon 3 of 4	ENSP00000406976.2	Q7L8W6-2
	DPH6	ENST00000896513.1		c.234C>G	p.Ser78Arg	missense	Exon 3 of 9	ENSP00000566572.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459326 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725888

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 85916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110164

Other (OTH) AF: 0.00 AC: 0 AN: 60258

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.16
Eigen_PC	Benign	-0.047
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		0.27
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.29
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.034	D
Polyphen		0.99	D
Vest4		0.64
MutPred		0.41		Gain of solvent accessibility (P = 0.0365)
MVP		0.58
MPC		0.70
ClinPred		1.0	D
GERP RS		-1.5
Varity_R		0.92
gMVP		0.82
Mutation Taster		=46/54	disease causing

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: rs748153954; hg19: chr15-35830553;