dbSNP rs5473: HP:p.Val124Val (chr16-72059118-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_005143.5(HP):c.372G>A(p.Val124Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,564,952 control chromosomes in the GnomAD database, including 689 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0064 ( 98 hom., cov: 28)

Exomes 𝑓: 0.0044 ( 591 hom. )

Consequence

HP
NM_005143.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.191

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP7

Synonymous conserved (PhyloP=0.191 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HP	NM_005143.5 link	c.372G>A	p.Val124Val	synonymous_variant	Exon 6 of 7	ENST00000355906.10	NP_005134.1	P00738-1Q6PEJ8
HP	NM_001126102.3 link	c.195G>A	p.Val65Val	synonymous_variant	Exon 4 of 5		NP_001119574.1	P00738-2Q6PEJ8
HP	NM_001318138.2 link	c.266-994G>A		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.372G>A	p.Val124Val	synonymous_variant	Exon 6 of 7	1	NM_005143.5	ENSP00000348170.5		P00738-1
TXNL4B	ENST00000562153.5 link	c.285-14761C>T		intron_variant	Intron 3 of 3	4		ENSP00000454635.2		H3BN11

Frequencies

GnomAD3 genomes

AF:

0.00640

AC:

909

AN:

142048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0346

Gnomad ASJ

AF:

0.00446

Gnomad EAS

AF:

0.0278

Gnomad SAS

AF:

0.00632

Gnomad FIN

AF:

0.000595

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.0112

GnomAD3 exomes

AF:

0.0119

AC:

2899

AN:

242614

Hom.:

257

AF XY:

0.00969

AC XY:

1278

AN XY:

131868

show subpopulations

Gnomad AFR exome

AF:

0.00380

Gnomad AMR exome

AF:

0.0557

Gnomad ASJ exome

AF:

0.00582

Gnomad EAS exome

AF:

0.0248

Gnomad SAS exome

AF:

0.00704

Gnomad FIN exome

AF:

0.00105

Gnomad NFE exome

AF:

0.00140

Gnomad OTH exome

AF:

0.00863

GnomAD4 exome

AF:

0.00445

AC:

6326

AN:

1422794

Hom.:

591

Cov.:

AF XY:

0.00425

AC XY:

3012

AN XY:

708566

show subpopulations

Gnomad4 AFR exome

AF:

0.00151

Gnomad4 AMR exome

AF:

0.0519

Gnomad4 ASJ exome

AF:

0.00494

Gnomad4 EAS exome

AF:

0.0375

Gnomad4 SAS exome

AF:

0.00646

Gnomad4 FIN exome

AF:

0.000985

Gnomad4 NFE exome

AF:

0.00136

Gnomad4 OTH exome

AF:

0.00491

GnomAD4 genome

AF:

0.00642

AC:

912

AN:

142158

Hom.:

Cov.:

AF XY:

0.00681

AC XY:

473

AN XY:

69500

show subpopulations

Gnomad4 AFR

AF:

0.00248

Gnomad4 AMR

AF:

0.0349

Gnomad4 ASJ

AF:

0.00446

Gnomad4 EAS

AF:

0.0277

Gnomad4 SAS

AF:

0.00633

Gnomad4 FIN

AF:

0.000595

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.0105

Alfa

AF:

0.00499

Hom.:

Asia WGS

AF:

0.00875

AC:

AN:

3444

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

7.7

DANN

Benign

0.76

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over