NM_005143.5:c.389A>G

Variant names:

Variant summary

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

The NM_005143.5(HP):c.389A>G(p.Glu130Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000319 in 1,565,628 control chromosomes in the GnomAD database, including 1 homozygotes. 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. E130K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000021 ( 1 hom. )

Consequence

HP
NM_005143.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.94

Variant links:

Genes affected

HP (HGNC:5141): (haptoglobin) This gene encodes a preproprotein, which is processed to yield both alpha and beta chains, which subsequently combine as a tetramer to produce haptoglobin. Haptoglobin functions to bind free plasma hemoglobin, which allows degradative enzymes to gain access to the hemoglobin, while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin. Mutations in this gene and/or its regulatory regions cause ahaptoglobinemia or hypohaptoglobinemia. This gene has also been linked to diabetic nephropathy, the incidence of coronary artery disease in type 1 diabetes, Crohn's disease, inflammatory disease behavior, primary sclerosing cholangitis, susceptibility to idiopathic Parkinson's disease, and a reduced incidence of Plasmodium falciparum malaria. The protein encoded also exhibits antimicrobial activity against bacteria. A similar duplicated gene is located next to this gene on chromosome 16. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2014]

HP links:

TXNL4B (HGNC:26041): (thioredoxin like 4B) Predicted to be involved in mRNA splicing, via spliceosome. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TXNL4B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HP	NM_005143.5 link	c.389A>G	p.Glu130Gly	missense_variant	Exon 6 of 7	ENST00000355906.10	NP_005134.1	P00738-1Q6PEJ8
HP	NM_001126102.3 link	c.212A>G	p.Glu71Gly	missense_variant	Exon 4 of 5		NP_001119574.1	P00738-2Q6PEJ8
HP	NM_001318138.2 link	c.266-977A>G		intron_variant	Intron 4 of 4		NP_001305067.1	P00738Q6PEJ8A0A0C4DGL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HP	ENST00000355906.10 link	c.389A>G	p.Glu130Gly	missense_variant	Exon 6 of 7	1	NM_005143.5	ENSP00000348170.5		P00738-1
TXNL4B	ENST00000562153.5 link	c.285-14778T>C		intron_variant	Intron 3 of 3	4		ENSP00000454635.2		H3BN11

Frequencies

GnomAD3 genomes

AF:

0.0000141

AC:

AN:

142136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000304

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000411

AC:

AN:

243088

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132134

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000211

AC:

AN:

1423492

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708876

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000511

GnomAD4 genome

AF:

0.0000141

AC:

AN:

142136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000304

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.389A>G (p.E130G) alteration is located in exon 6 (coding exon 6) of the HP gene. This alteration results from a A to G substitution at nucleotide position 389, causing the glutamic acid (E) at amino acid position 130 to be replaced by a glycine (G). 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

0.13

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.68

.;D;.;T;.;.;.;T

Eigen

Benign

0.078

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.76

.;T;T;T;T;T;T;T

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.48

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.8

.;M;.;.;.;.;.;.

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.3

D;D;D;.;D;.;D;.

REVEL

Benign

0.14

Sift

Uncertain

0.013

D;D;D;.;D;.;D;.

Sift4G

Uncertain

0.014

D;D;D;D;D;D;D;D

Polyphen

0.23

.;B;.;.;.;.;.;.

Vest4

0.32

MutPred

0.50

.;Loss of stability (P = 0.0114);.;.;.;.;.;.;

MVP

0.83

MPC

0.32

ClinPred

0.95

GERP RS

4.2

Varity_R

0.24

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over