chr4-144646832-A-T

Position:

• chr4-144646832-A-T

Variant summary

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

The NM_022475.3(HHIP):​c.157A>T​(p.Arg53Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HHIP NM_022475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

Genes affected

HHIP (HGNC:14866): (hedgehog interacting protein) This gene encodes a member of the hedgehog-interacting protein (HHIP) family. The hedgehog (HH) proteins are evolutionarily conserved protein, which are important morphogens for a wide range of developmental processes, including anteroposterior patterns of limbs and regulation of left-right asymmetry in embryonic development. Multiple cell-surface receptors are responsible for transducing and/or regulating HH signals. The HHIP encoded by this gene is a highly conserved, vertebrate-specific inhibitor of HH signaling. It interacts with all three HH family members, SHH, IHH and DHH. Two single nucleotide polymorphisms (SNPs) near this gene are significantly associated with risk of chronic obstructive pulmonary disease (COPD). A single nucleotide polymorphism in this gene is also strongly associated with human height.[provided by RefSeq, Feb 2011]

HHIP-AS1 (HGNC:44182): (HHIP antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HHIP	NM_022475.3	c.157A>T	p.Arg53Trp	missense_variant	1/13	ENST00000296575.8	NP_071920.1
HHIP	XM_005263178.6	c.157A>T	p.Arg53Trp	missense_variant	1/14		XP_005263235.1
HHIP	XM_006714288.5	c.157A>T	p.Arg53Trp	missense_variant	1/14		XP_006714351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HHIP	ENST00000296575.8	c.157A>T	p.Arg53Trp	missense_variant	1/13	1	NM_022475.3	ENSP00000296575	P1
HHIP-AS1	ENST00000512359.1	n.284-3098T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2023

The c.157A>T (p.R53W) alteration is located in exon 1 (coding exon 1) of the HHIP gene. This alteration results from a A to T substitution at nucleotide position 157, causing the arginine (R) at amino acid position 53 to be replaced by a tryptophan (W). 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	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.57	N;N
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.38		Gain of glycosylation at S57 (P = 0.0017);Gain of glycosylation at S57 (P = 0.0017);
MVP		0.62
MPC		0.79
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.40
gMVP		0.84

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: chr4-145567984;