rs2070937

Variant names:

• chr16-72055841-A-G
• rs2070937
• NM_005143.5:c.6-320A>G

Variant summary

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

The NM_005143.5(HP):​c.6-320A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 384,938 control chromosomes in the GnomAD database, including 60,709 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 0.56 (23944 hom., cov: 30)
  • Exomes 𝑓: 0.55 (36765 hom.)
• Consequence: HP NM_005143.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08
• Publications: 16 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HP	NM_005143.5	c.6-320A>G		intron_variant	Intron 1 of 6	ENST00000355906.10	NP_005134.1
HP	NM_001126102.3	c.6-320A>G		intron_variant	Intron 1 of 4		NP_001119574.1
HP	NM_001318138.2	c.6-320A>G		intron_variant	Intron 1 of 4		NP_001305067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HP	ENST00000355906.10	c.6-320A>G		intron_variant	Intron 1 of 6	1	NM_005143.5	ENSP00000348170.5
ENSG00000310525	ENST00000562153.6	n.285-11484T>C		intron_variant	Intron 3 of 5	4		ENSP00000454635.2

Frequencies

GnomAD3 genomes AF: 0.557 AC: 84429 AN: 151608 Hom.: 23921 Cov.: 30

Gnomad AFR AF: 0.624

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.653

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.567

GnomAD4 exome AF: 0.553 AC: 128913 AN: 233210 Hom.: 36765 Cov.: 3 AF XY: 0.563 AC XY: 71549 AN XY: 127148

African (AFR) AF: 0.624 AC: 3941 AN: 6316

American (AMR) AF: 0.397 AC: 5076 AN: 12798

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 4057 AN: 5758

East Asian (EAS) AF: 0.357 AC: 3758 AN: 10516

South Asian (SAS) AF: 0.648 AC: 27646 AN: 42690

European-Finnish (FIN) AF: 0.559 AC: 5938 AN: 10630

Middle Eastern (MID) AF: 0.627 AC: 529 AN: 844

European-Non Finnish (NFE) AF: 0.541 AC: 71464 AN: 132034

Other (OTH) AF: 0.560 AC: 6504 AN: 11624

GnomAD4 genome AF: 0.557 AC: 84497 AN: 151728 Hom.: 23944 Cov.: 30 AF XY: 0.556 AC XY: 41215 AN XY: 74096

African (AFR) AF: 0.624 AC: 25837 AN: 41386

American (AMR) AF: 0.445 AC: 6785 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 2382 AN: 3472

East Asian (EAS) AF: 0.359 AC: 1821 AN: 5072

South Asian (SAS) AF: 0.651 AC: 3132 AN: 4808

European-Finnish (FIN) AF: 0.572 AC: 6014 AN: 10516

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36798 AN: 67932

Other (OTH) AF: 0.567 AC: 1191 AN: 2102

Alfa AF: 0.547 Hom.: 50088

Bravo AF: 0.544

Asia WGS AF: 0.514 AC: 1792 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.053
DANN	Benign	0.39
PhyloP100		-2.1
PromoterAI		0.0016	Neutral
Mutation Taster		=100/0	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: rs2070937; hg19: chr16-72089740; COSMIC: COSV63326413; COSMIC: COSV63326413;