1-43971407-C-A

Variant names:

• chr1-43971407-C-A
• rs766208949
• NM_001384.5:c.505C>A

Variant summary

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

The NM_001384.5(DPH2):​c.505C>A​(p.Arg169Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R169C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DPH2 NM_001384.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.455
• Publications: 0 publications found

Genes affected

DPH2 (HGNC:3004): (diphthamide biosynthesis 2) This gene is one of two human genes similar to the yeast gene dph2. The yeast gene was identified by its ability to complement a diphthamide mutant strain, and thus probably functions in diphthamide biosynthesis. Diphthamide is a post-translationally modified histidine residue present in elongation factor 2 (EF2) that is the target of diphtheria toxin ADP-ribosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

ENSG00000285649 (HGNC:):

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=0.1266563).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384.5. 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
	DPH2	NM_001384.5	MANE Select	c.505C>A	p.Arg169Ser	missense	Exon 4 of 6	NP_001375.2
	DPH2	NM_001319165.2		c.277C>A	p.Arg93Ser	missense	Exon 4 of 6	NP_001306094.1	B3KRB8
	DPH2	NM_001319168.2		c.277C>A	p.Arg93Ser	missense	Exon 4 of 6	NP_001306097.1	B3KRB8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH2	ENST00000255108.8	TSL:1 MANE Select	c.505C>A	p.Arg169Ser	missense	Exon 4 of 6	ENSP00000255108.3	Q9BQC3-1
	DPH2	ENST00000922599.1		c.523C>A	p.Arg175Ser	missense	Exon 4 of 6	ENSP00000592658.1
	DPH2	ENST00000955917.1		c.505C>A	p.Arg169Ser	missense	Exon 4 of 6	ENSP00000625976.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443436 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 715966

⚠️ 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: 32706

American (AMR) AF: 0.00 AC: 0 AN: 42438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39372

South Asian (SAS) AF: 0.00 AC: 0 AN: 85004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1100718

Other (OTH) AF: 0.00 AC: 0 AN: 59406

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.045	N
PhyloP100		0.46
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.11
Sift	Benign	0.69	T
Sift4G	Benign	0.43	T
Polyphen		0.36	B
Vest4		0.30
MutPred		0.48		Gain of glycosylation at T166 (P = 0.0738)
MVP		0.37
MPC		0.28
ClinPred		0.30	T
GERP RS		3.8
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.66
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs766208949; hg19: chr1-44437079;