NM_005143.5:c.19G>A

Variant names:

• chr16-72056174-G-A
• rs200346377
• NM_005143.5:c.19G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005143.5(HP):​c.19G>A​(p.Val7Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HP NM_005143.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24048457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HP	NM_005143.5	c.19G>A	p.Val7Ile	missense_variant	Exon 2 of 7	ENST00000355906.10	NP_005134.1
HP	NM_001126102.3	c.19G>A	p.Val7Ile	missense_variant	Exon 2 of 5		NP_001119574.1
HP	NM_001318138.2	c.19G>A	p.Val7Ile	missense_variant	Exon 2 of 5		NP_001305067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HP	ENST00000355906.10	c.19G>A	p.Val7Ile	missense_variant	Exon 2 of 7	1	NM_005143.5	ENSP00000348170.5
TXNL4B	ENST00000562153.5	c.285-11817C>T		intron_variant	Intron 3 of 3	4		ENSP00000454635.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249510 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135362

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461784 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.33	.;T;.;T;.;.;.;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.71	.;T;T;T;T;T;T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.6	M;M;M;.;.;.;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.17	N;N;N;.;N;.;N;N;.
REVEL	Benign	0.26
Sift	Uncertain	0.014	D;D;D;.;D;.;D;D;.
Sift4G	Uncertain	0.053	T;D;T;D;T;D;D;T;D
Polyphen		0.98	.;D;.;.;.;.;.;.;.
Vest4		0.39
MutPred		0.41		Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);
MVP		0.72
MPC		0.21
ClinPred		0.25	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095
gMVP		0.065

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: rs200346377; hg19: chr16-72090073;