7-35670259-T-G

Position:

• chr7-35670259-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022373.5(HERPUD2):​c.295A>C​(p.Thr99Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HERPUD2 NM_022373.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

Genes affected

HERPUD2 (HGNC:21915): (HERPUD family member 2) Predicted to be involved in endoplasmic reticulum unfolded protein response. Predicted to act upstream of or within spermatogenesis. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07758364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HERPUD2	NM_022373.5	c.295A>C	p.Thr99Pro	missense_variant	4/9	ENST00000311350.8	NP_071768.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERPUD2	ENST00000311350.8	c.295A>C	p.Thr99Pro	missense_variant	4/9	1	NM_022373.5	ENSP00000310729.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1440632 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 716930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000514

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2023

The c.295A>C (p.T99P) alteration is located in exon 4 (coding exon 3) of the HERPUD2 gene. This alteration results from a A to C substitution at nucleotide position 295, causing the threonine (T) at amino acid position 99 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0060	T;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.57	.;T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.017
Sift	Benign	0.069	T;T;T
Sift4G	Benign	0.32	T;T;.
Polyphen		0.17	B;B;.
Vest4		0.20
MutPred		0.17		Loss of phosphorylation at T99 (P = 0.018);Loss of phosphorylation at T99 (P = 0.018);.;
MVP		0.26
MPC		0.44
ClinPred		0.75	D
GERP RS		1.9
Varity_R		0.16
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs1785616570; hg19: chr7-35709869;