16-72060151-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005143.5(HP):c.482G>A(p.Arg161Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: HP NM_005143.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HP	NM_005143.5	c.482G>A	p.Arg161Gln	missense_variant	7/7	ENST00000355906.10
HP	NM_001126102.3	c.305G>A	p.Arg102Gln	missense_variant	5/5
HP	NM_001318138.2	c.305G>A	p.Arg102Gln	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HP	ENST00000355906.10	c.482G>A	p.Arg161Gln	missense_variant	7/7	1	NM_005143.5	A2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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: 0.0000588

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000656 AC: 16 AN: 244044 Hom.: 0 AF XY: 0.0000678 AC XY: 9 AN XY: 132748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000989

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000545

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000684 AC: 100 AN: 1461600 Hom.: 0 Cov.: 31 AF XY: 0.0000646 AC XY: 47 AN XY: 727092

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152154 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74374

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000242

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.0000497 AC: 6

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

May 10, 2022

The c.482G>A (p.R161Q) 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 482, causing the arginine (R) at amino acid position 161 to be replaced by a glutamine (Q). 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	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D;D;.;D;.;.;D
Sift	Uncertain	0.0090	D;D;.;D;.;.;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.;.
Vest4		0.69
MVP		0.97
MPC		0.93
ClinPred		0.85	D
GERP RS		4.9
Varity_R		0.82
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs368624883; hg19: chr16-72094050; COSMIC: COSV100577630; COSMIC: COSV100577630;