1-100992721-G-T

Variant names:

• chr1-100992721-G-T
• rs916805426
• NM_015958.3:c.550C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_015958.3(DPH5):​c.550C>A​(p.Pro184Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P184A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DPH5 NM_015958.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.16
• Publications: 0 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 3 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.

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.550C>A	p.Pro184Thr	missense	Exon 7 of 8	NP_057042.2	Q9H2P9-1
	DPH5	NM_001077394.2		c.550C>A	p.Pro184Thr	missense	Exon 7 of 8	NP_001070862.1	Q9H2P9-1
	DPH5	NM_001077395.2		c.550C>A	p.Pro184Thr	missense	Exon 7 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.550C>A	p.Pro184Thr	missense	Exon 7 of 8	ENSP00000359127.3	Q9H2P9-1
	DPH5	ENST00000427040.3	TSL:1	c.550C>A	p.Pro184Thr	missense	Exon 6 of 7	ENSP00000394364.3	Q9H2P9-1
	DPH5	ENST00000342173.11	TSL:1	c.550C>A	p.Pro184Thr	missense	Exon 7 of 8	ENSP00000339630.7	Q9H2P9-6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460870 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726752

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

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

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111298

Other (OTH) AF: 0.0000166 AC: 1 AN: 60352

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.65		Gain of phosphorylation at P184 (P = 0.0238)
MVP		0.87
MPC		0.41
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.73
gMVP		0.73
Mutation Taster		=10/90	disease causing

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: rs916805426; hg19: chr1-101458277;