16-72057415-A-C

Variant names:

• chr16-72057415-A-C
• rs137853233
• NM_005143.5:c.214A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_005143.5(HP):​c.214A>C​(p.Lys72Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K72E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: HP NM_005143.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2714107).

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.214A>C	p.Lys72Gln	missense	Exon 4 of 7	NP_005134.1	P00738-1
	HP	NM_001318138.2		c.214A>C	p.Lys72Gln	missense	Exon 4 of 5	NP_001305067.1	A0A0C4DGL8
	HP	NM_001126102.3		c.190+784A>C		intron	N/A	NP_001119574.1	P00738-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HP	ENST00000355906.10	TSL:1 MANE Select	c.214A>C	p.Lys72Gln	missense	Exon 4 of 7	ENSP00000348170.5	P00738-1
	HP	ENST00000565574.5	TSL:1	c.214A>C	p.Lys72Gln	missense	Exon 4 of 5	ENSP00000454966.1	A0A0C4DGL8
	HP	ENST00000398131.6	TSL:1	c.190+784A>C		intron	N/A	ENSP00000381199.2	P00738-2

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 949058 Hom.: 0 Cov.: 14 AF XY: 0.00000207 AC XY: 1 AN XY: 482782

African (AFR) AF: 0.00 AC: 0 AN: 23260

American (AMR) AF: 0.00 AC: 0 AN: 27952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21716

East Asian (EAS) AF: 0.0000318 AC: 1 AN: 31440

South Asian (SAS) AF: 0.00 AC: 0 AN: 73114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4648

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 677394

Other (OTH) AF: 0.00 AC: 0 AN: 42928

GnomAD4 genome Cov.: 19

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.52
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.079
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.16
Sift	Benign	0.40	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.31
MutPred		0.49		Loss of ubiquitination at K72 (P = 0.0244)
MVP		0.57
MPC		0.48
ClinPred		0.42	T
GERP RS		3.2
Varity_R		0.12
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs137853233; hg19: chr16-72091314;