chr16-72056201-C-A

Variant names:

• chr16-72056201-C-A
• rs753062127
• NM_005143.5:c.46C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005143.5(HP):​c.46C>A​(p.Leu16Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HP NM_005143.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40280017).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005143.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HP	NM_005143.5	MANE Select	c.46C>A	p.Leu16Ile	missense	Exon 2 of 7	NP_005134.1	P00738-1
	HP	NM_001126102.3		c.46C>A	p.Leu16Ile	missense	Exon 2 of 5	NP_001119574.1	P00738-2
	HP	NM_001318138.2		c.46C>A	p.Leu16Ile	missense	Exon 2 of 5	NP_001305067.1	A0A0C4DGL8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HP	ENST00000355906.10	TSL:1 MANE Select	c.46C>A	p.Leu16Ile	missense	Exon 2 of 7	ENSP00000348170.5	P00738-1
	HP	ENST00000398131.6	TSL:1	c.46C>A	p.Leu16Ile	missense	Exon 2 of 5	ENSP00000381199.2	P00738-2
	HP	ENST00000565574.5	TSL:1	c.46C>A	p.Leu16Ile	missense	Exon 2 of 5	ENSP00000454966.1	A0A0C4DGL8

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249448 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000342 AC: 5 AN: 1461792 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.41
Sift	Benign	0.032	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.39		Loss of sheet (P = 0.1158)
MVP		0.80
MPC		0.34
ClinPred		0.49	T
GERP RS		3.9
PromoterAI		0.0034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.11

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

Other links and lift over

dbSNP: rs753062127; hg19: chr16-72090100;