16-72056553-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005143.5(HP):c.112G>A(p.Glu38Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,488,700 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 21)
  • Exomes 𝑓: 0.0044 (15 hom.)
• Consequence: HP NM_005143.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0730

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006028712).
• BP6: Variant 16-72056553-G-A is Benign according to our data. Variant chr16-72056553-G-A is described in ClinVar as [Benign]. Clinvar id is 777878.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HP	NM_005143.5	c.112G>A	p.Glu38Lys	missense_variant	3/7	ENST00000355906.10
HP	NM_001126102.3	c.112G>A	p.Glu38Lys	missense_variant	3/5
HP	NM_001318138.2	c.112G>A	p.Glu38Lys	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HP	ENST00000355906.10	c.112G>A	p.Glu38Lys	missense_variant	3/7	1	NM_005143.5	A2

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 394 AN: 135384 Hom.: 1 Cov.: 21

Gnomad AFR AF: 0.000940

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00611

Gnomad ASJ AF: 0.000302

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.00290

GnomAD3 exomes AF: 0.00296 AC: 475 AN: 160454 Hom.: 2 AF XY: 0.00297 AC XY: 253 AN XY: 85232

Gnomad AFR exome AF: 0.000764

Gnomad AMR exome AF: 0.00505

Gnomad ASJ exome AF: 0.000826

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000129

Gnomad FIN exome AF: 0.000352

Gnomad NFE exome AF: 0.00496

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00439 AC: 5945 AN: 1353208 Hom.: 15 Cov.: 22 AF XY: 0.00425 AC XY: 2849 AN XY: 669948

Gnomad4 AFR exome AF: 0.000586

Gnomad4 AMR exome AF: 0.00493

Gnomad4 ASJ exome AF: 0.000563

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000115

Gnomad4 FIN exome AF: 0.000404

Gnomad4 NFE exome AF: 0.00529

Gnomad4 OTH exome AF: 0.00378

GnomAD4 genome AF: 0.00291 AC: 394 AN: 135492 Hom.: 1 Cov.: 21 AF XY: 0.00263 AC XY: 171 AN XY: 65020

Gnomad4 AFR AF: 0.000937

Gnomad4 AMR AF: 0.00611

Gnomad4 ASJ AF: 0.000302

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00431

Gnomad4 OTH AF: 0.00287

Alfa AF: 0.00278 Hom.: 1

Bravo AF: 0.00344

ESP6500AA AF: 0.000875 AC: 3

ESP6500EA AF: 0.00450 AC: 35

ExAC AF: 0.00168 AC: 189

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	3.6
Dann	Benign	0.70
DEOGEN2	Benign	0.30	T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.023	N
LIST_S2	Uncertain	0.88	D;T;T;T
MetaRNN	Benign	0.0060	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.34	N;N;.;N
REVEL	Benign	0.14
Sift	Benign	0.10	T;T;.;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.17	B;.;.;.
Vest4		0.22
MVP		0.19
MPC		0.28
ClinPred		0.0062	T
GERP RS		-2.3
Varity_R		0.029
gMVP		0.35

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: rs201773535; hg19: chr16-72090452;