rs758871223

Variant names:

• chr1-100990580-T-G
• rs758871223
• NM_015958.3:c.686A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_015958.3(DPH5):​c.686A>C​(p.Asp229Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,856 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D229N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DPH5 NM_015958.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.07
• Publications: 3 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 2 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=0.36804006).

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.686A>C	p.Asp229Ala	missense	Exon 8 of 8	NP_057042.2	Q9H2P9-1
	DPH5	NM_001077394.2		c.686A>C	p.Asp229Ala	missense	Exon 8 of 8	NP_001070862.1	Q9H2P9-1
	DPH5	NM_001077395.2		c.683A>C	p.Asp228Ala	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.686A>C	p.Asp229Ala	missense	Exon 8 of 8	ENSP00000359127.3	Q9H2P9-1
	DPH5	ENST00000427040.3	TSL:1	c.686A>C	p.Asp229Ala	missense	Exon 7 of 7	ENSP00000394364.3	Q9H2P9-1
	DPH5	ENST00000342173.11	TSL:1	c.683A>C	p.Asp228Ala	missense	Exon 8 of 8	ENSP00000339630.7	Q9H2P9-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249484 AF XY: 0.00000739

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

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	Benign	0.18
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.1
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.21
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.043	D
Polyphen		0.87	P
Vest4		0.49
MutPred		0.45		Gain of MoRF binding (P = 0.0354)
MVP		0.67
MPC		0.49
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.55
gMVP		0.69
Mutation Taster		=58/42	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: rs758871223; hg19: chr1-101456136;