16-72060181-G-A

Variant summary

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

The NM_005143.5(HP):c.512G>A(p.Gly171Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: HP NM_005143.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

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]

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]

ACMG classification

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/exons	MANE	UniProt
HP	NM_005143.5	c.512G>A	p.Gly171Asp	missense_variant	7/7	ENST00000355906.10
HP	NM_001126102.3	c.335G>A	p.Gly112Asp	missense_variant	5/5
HP	NM_001318138.2	c.335G>A	p.Gly112Asp	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HP	ENST00000355906.10	c.512G>A	p.Gly171Asp	missense_variant	7/7	1	NM_005143.5	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727192

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: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.512G>A (p.G171D) alteration is located in exon 7 (coding exon 7) of the HP gene. This alteration results from a G to A substitution at nucleotide position 512, causing the glycine (G) at amino acid position 171 to be replaced by an aspartic acid (D). 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	0.20
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	23
Dann	Benign	0.94
Eigen	Benign	0.13
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationTaster	Benign	0.98	D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.7	D;D;.;D;.;.;D
Sift	Pathogenic	0.0	D;D;.;D;.;.;D
Sift4G	Uncertain	0.024	D;D;T;D;D;T;D
Polyphen		0.47	.;P;.;.;.;.;.
Vest4		0.19
MutPred		0.85		.;Gain of solvent accessibility (P = 0.006);.;.;.;.;.;
MVP		0.94
MPC		0.63
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.69
gMVP		0.88

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

Other links and lift over

dbSNP: rs2041519284; hg19: chr16-72094080;