rs5473

Variant names:

• chr16-72059118-G-A
• rs5473
• NM_005143.5:c.372G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.191
• Publications: 11 publications found

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]

ENSG00000310525 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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	c.372G>A	p.Val124Val	synonymous_variant	Exon 6 of 7	ENST00000355906.10	NP_005134.1
HP	NM_001126102.3	c.195G>A	p.Val65Val	synonymous_variant	Exon 4 of 5		NP_001119574.1
HP	NM_001318138.2	c.266-994G>A		intron_variant	Intron 4 of 4		NP_001305067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HP	ENST00000355906.10	c.372G>A	p.Val124Val	synonymous_variant	Exon 6 of 7	1	NM_005143.5	ENSP00000348170.5
ENSG00000310525	ENST00000562153.6	n.285-14761C>T		intron_variant	Intron 3 of 5	4		ENSP00000454635.2

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 909 AN: 142048 Hom.: 97 Cov.: 28

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

GnomAD2 exomes AF: 0.0119 AC: 2899 AN: 242614 AF XY: 0.00969

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 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.: 30 AF XY: 0.00425 AC XY: 3012 AN XY: 708566

African (AFR) AF: 0.00151 AC: 44 AN: 29082

American (AMR) AF: 0.0519 AC: 2298 AN: 44238

Ashkenazi Jewish (ASJ) AF: 0.00494 AC: 126 AN: 25494

East Asian (EAS) AF: 0.0375 AC: 1486 AN: 39660

South Asian (SAS) AF: 0.00646 AC: 554 AN: 85702

European-Finnish (FIN) AF: 0.000985 AC: 51 AN: 51760

Middle Eastern (MID) AF: 0.000541 AC: 3 AN: 5548

European-Non Finnish (NFE) AF: 0.00136 AC: 1476 AN: 1082678

Other (OTH) AF: 0.00491 AC: 288 AN: 58632

GnomAD4 genome AF: 0.00642 AC: 912 AN: 142158 Hom.: 98 Cov.: 28 AF XY: 0.00681 AC XY: 473 AN XY: 69500

African (AFR) AF: 0.00248 AC: 87 AN: 35072

American (AMR) AF: 0.0349 AC: 515 AN: 14758

Ashkenazi Jewish (ASJ) AF: 0.00446 AC: 15 AN: 3362

East Asian (EAS) AF: 0.0277 AC: 143 AN: 5170

South Asian (SAS) AF: 0.00633 AC: 30 AN: 4740

European-Finnish (FIN) AF: 0.000595 AC: 6 AN: 10082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00144 AC: 95 AN: 65820

Other (OTH) AF: 0.0105 AC: 21 AN: 1992

Alfa AF: 0.00499 Hom.: 25

Asia WGS AF: 0.00875 AC: 30 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
PhyloP100		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs5473; hg19: chr16-72093017; COSMIC: COSV63325658; COSMIC: COSV63325658;