16-56935236-G-T

Variant names:

• chr16-56935236-G-T
• rs2217332
• NM_014685.4:c.149G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014685.4(HERPUD1):​c.149G>T​(p.Arg50Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HERPUD1 NM_014685.4 missense, splice_region
• Scores: Splicing: ADA: 0.00001148
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101
• Publications: 0 publications found

Genes affected

HERPUD1 (HGNC:13744): (homocysteine inducible ER protein with ubiquitin like domain 1) The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the ER stress response. This response includes the inhibition of translation to prevent further accumulation of unfolded proteins, the increased expression of proteins involved in polypeptide folding, known as the unfolded protein response (UPR), and the destruction of misfolded proteins by the ER-associated protein degradation (ERAD) system. This gene may play a role in both UPR and ERAD. Its expression is induced by UPR and it has an ER stress response element in its promoter region while the encoded protein has an N-terminal ubiquitin-like domain which may interact with the ERAD system. This protein has been shown to interact with presenilin proteins and to increase the level of amyloid-beta protein following its overexpression. Alternative splicing of this gene produces multiple transcript variants encoding different isoforms. The full-length nature of all transcript variants has not been determined. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079200834).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014685.4. 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
	HERPUD1	NM_014685.4	MANE Select	c.149G>T	p.Arg50Leu	missense splice_region	Exon 2 of 8	NP_055500.1
	HERPUD1	NM_001010989.3		c.149G>T	p.Arg50Leu	missense splice_region	Exon 2 of 8	NP_001010989.1
	HERPUD1	NM_001436349.1		c.149G>T	p.Arg50Leu	missense splice_region	Exon 2 of 8	NP_001423278.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERPUD1	ENST00000439977.7	TSL:1 MANE Select	c.149G>T	p.Arg50Leu	missense splice_region	Exon 2 of 8	ENSP00000409555.2
	HERPUD1	ENST00000300302.9	TSL:1	c.149G>T	p.Arg50Leu	missense splice_region	Exon 2 of 8	ENSP00000300302.5
	HERPUD1	ENST00000344114.8	TSL:1	c.149G>T	p.Arg50Leu	missense splice_region	Exon 2 of 6	ENSP00000340931.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.79
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.10
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.11
Sift	Benign	0.60	T
Sift4G	Benign	0.78	T
Polyphen		0.0070	B
Vest4		0.14
MutPred		0.50		Loss of disorder (P = 0.0641)
MVP		0.60
MPC		0.25
ClinPred		0.098	T
GERP RS		3.1
PromoterAI		-0.016	Neutral
Varity_R		0.10
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.010
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: rs2217332; hg19: chr16-56969148;