chr16-72060337-T-C

Variant names:

• chr16-72060337-T-C
• NM_005143.5:c.668T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005143.5(HP):​c.668T>C​(p.Leu223Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,852 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: HP NM_005143.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HP	NM_005143.5	c.668T>C	p.Leu223Pro	missense_variant	Exon 7 of 7	ENST00000355906.10	NP_005134.1
HP	NM_001126102.3	c.491T>C	p.Leu164Pro	missense_variant	Exon 5 of 5		NP_001119574.1
HP	NM_001318138.2	c.491T>C	p.Leu164Pro	missense_variant	Exon 5 of 5		NP_001305067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HP	ENST00000355906.10	c.668T>C	p.Leu223Pro	missense_variant	Exon 7 of 7	1	NM_005143.5	ENSP00000348170.5
TXNL4B	ENST00000562153.5	c.285-15980A>G		intron_variant	Intron 3 of 3	4		ENSP00000454635.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000611 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.668T>C (p.L223P) alteration is located in exon 7 (coding exon 7) of the HP gene. This alteration results from a T to C substitution at nucleotide position 668, causing the leucine (L) at amino acid position 223 to be replaced by a proline (P). 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.80	.;D;T;.;.;.;T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.6	.;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D;D;.;D;D;.;.;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;.;D;D;.;.;D
Sift4G	Benign	0.072	T;D;T;T;T;D;T;T
Polyphen		1.0	.;D;.;.;.;.;.;.
Vest4		0.57
MutPred		0.67		.;Loss of stability (P = 0.014);.;.;.;.;.;.;
MVP		0.96
MPC		1.1
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.90
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-72094236;