7-35670232-C-T

Variant names:

• chr7-35670232-C-T
• rs3779234
• NM_022373.5:c.322G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022373.5(HERPUD2):​c.322G>A​(p.Ala108Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,553,080 control chromosomes in the GnomAD database, including 104,106 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. A108G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.31 (7958 hom., cov: 27)
  • Exomes 𝑓: 0.37 (96148 hom.)
• Consequence: HERPUD2 NM_022373.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.963
• Publications: 40 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026303232).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022373.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERPUD2	NM_022373.5	MANE Select	c.322G>A	p.Ala108Thr	missense	Exon 4 of 9	NP_071768.3
	HERPUD2	NM_001438072.1		c.322G>A	p.Ala108Thr	missense	Exon 3 of 8	NP_001425001.1
	HERPUD2	NM_001438070.1		c.148-2644G>A		intron	N/A	NP_001424999.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERPUD2	ENST00000311350.8	TSL:1 MANE Select	c.322G>A	p.Ala108Thr	missense	Exon 4 of 9	ENSP00000310729.3
	HERPUD2	ENST00000396081.5	TSL:1	c.322G>A	p.Ala108Thr	missense	Exon 3 of 8	ENSP00000379390.1
	HERPUD2	ENST00000413517.1	TSL:5	c.244G>A	p.Ala82Thr	missense	Exon 2 of 5	ENSP00000391015.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 46545 AN: 148874 Hom.: 7958 Cov.: 27

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.345

GnomAD2 exomes AF: 0.340 AC: 80514 AN: 236682 AF XY: 0.348

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.295

Gnomad ASJ exome AF: 0.407

Gnomad EAS exome AF: 0.262

Gnomad FIN exome AF: 0.332

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.365 AC: 512623 AN: 1404088 Hom.: 96148 Cov.: 25 AF XY: 0.367 AC XY: 256465 AN XY: 699758

African (AFR) AF: 0.157 AC: 4982 AN: 31644

American (AMR) AF: 0.302 AC: 12671 AN: 41946

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 10173 AN: 25214

East Asian (EAS) AF: 0.255 AC: 9743 AN: 38248

South Asian (SAS) AF: 0.349 AC: 27988 AN: 80176

European-Finnish (FIN) AF: 0.331 AC: 17286 AN: 52248

Middle Eastern (MID) AF: 0.412 AC: 2321 AN: 5634

European-Non Finnish (NFE) AF: 0.379 AC: 406346 AN: 1070896

Other (OTH) AF: 0.364 AC: 21113 AN: 58082

GnomAD4 genome AF: 0.313 AC: 46561 AN: 148992 Hom.: 7958 Cov.: 27 AF XY: 0.310 AC XY: 22482 AN XY: 72478

African (AFR) AF: 0.171 AC: 6883 AN: 40308

American (AMR) AF: 0.325 AC: 4804 AN: 14786

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1382 AN: 3446

East Asian (EAS) AF: 0.254 AC: 1295 AN: 5108

South Asian (SAS) AF: 0.344 AC: 1601 AN: 4650

European-Finnish (FIN) AF: 0.338 AC: 3416 AN: 10120

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.384 AC: 25835 AN: 67322

Other (OTH) AF: 0.343 AC: 705 AN: 2056

Alfa AF: 0.365 Hom.: 33030

Bravo AF: 0.305

TwinsUK AF: 0.390 AC: 1447

ALSPAC AF: 0.382 AC: 1474

ESP6500AA AF: 0.176 AC: 775

ESP6500EA AF: 0.386 AC: 3319

ExAC AF: 0.335 AC: 40690

Asia WGS AF: 0.316 AC: 1099 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.00017	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.090	N
PhyloP100		0.96
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.013
Sift	Benign	0.30	T
Sift4G	Benign	0.53	T
Polyphen		0.010	B
Vest4		0.024
MPC		0.28
ClinPred		0.0057	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.23
Mutation Taster		=92/8	polymorphism (auto)

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: rs3779234; hg19: chr7-35709842; COSMIC: COSV60943904; COSMIC: COSV60943904;