NM_015958.3:c.791T>C

Variant names:

• chr1-100990475-A-G
• rs200190622
• NM_015958.3:c.791T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_015958.3(DPH5):​c.791T>C​(p.Met264Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. M264R) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DPH5 NM_015958.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.18
• Publications: 1 publications found

Genes affected

DPH5 (HGNC:24270): (diphthamide biosynthesis 5) This gene encodes a component of the diphthamide synthesis pathway. Diphthamide is a post-translationally modified histidine residue found only on translation elongation factor 2. It is conserved from archaebacteria to humans, and is targeted by diphtheria toxin and Pseudomonas exotoxin A to halt cellular protein synthesis. The yeast and Chinese hamster homologs of this protein catalyze the trimethylation of the histidine residue on elongation factor 2, resulting in a diphthine moiety that is subsequently amidated to yield diphthamide. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SLC30A7 (HGNC:19306): (solute carrier family 30 member 7) Zinc functions as a cofactor for numerous enzymes, nuclear factors, and hormones and as an intra- and intercellular signal ion. Members of the zinc transporter (ZNT)/SLC30 subfamily of the cation diffusion facilitator family, such as SLC30A7, permit cellular efflux of zinc (Seve et al., 2004 [PubMed 15154973]).[supplied by OMIM, Mar 2008]

SLC30A7 Gene-Disease associations (from GenCC):

• Joubert syndrome

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.48136 (below the threshold of 3.09). Trascript score misZ: 0.75264 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties.
• BP4: Computational evidence support a benign effect (MetaRNN=0.069241256).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015958.3. 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
	DPH5	NM_015958.3	MANE Select	c.791T>C	p.Met264Thr	missense	Exon 8 of 8	NP_057042.2	Q9H2P9-1
	DPH5	NM_001077394.2		c.791T>C	p.Met264Thr	missense	Exon 8 of 8	NP_001070862.1	Q9H2P9-1
	DPH5	NM_001077395.2		c.788T>C	p.Met263Thr	missense	Exon 8 of 8	NP_001070863.1	Q9H2P9-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH5	ENST00000370109.8	TSL:1 MANE Select	c.791T>C	p.Met264Thr	missense	Exon 8 of 8	ENSP00000359127.3	Q9H2P9-1
	DPH5	ENST00000427040.3	TSL:1	c.791T>C	p.Met264Thr	missense	Exon 7 of 7	ENSP00000394364.3	Q9H2P9-1
	DPH5	ENST00000342173.11	TSL:1	c.788T>C	p.Met263Thr	missense	Exon 8 of 8	ENSP00000339630.7	Q9H2P9-6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74344

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	13
DANN	Benign	0.75
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.76	N
PhyloP100		2.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.037
Sift	Benign	0.59	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.30		Gain of glycosylation at M264 (P = 0.0525)
MVP		0.33
MPC		0.12
ClinPred		0.048	T
GERP RS		2.2
Varity_R		0.051
gMVP		0.28
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200190622; hg19: chr1-101456031;