4-144652792-T-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_022475.3(HHIP):c.467T>C(p.Ile156Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,569,450 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: 𝑓 0.00070 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

HHIP
NM_022475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

Variant links:

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 links:

ENSG00000285713 (HGNC:):

ENSG00000285713 links:

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

HHIP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.28082508).

BS2

High AC in GnomAd4 at 98 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHIP	NM_022475.3 link	c.467T>C	p.Ile156Thr	missense_variant	Exon 2 of 13	ENST00000296575.8	NP_071920.1	Q96QV1-1
HHIP	XM_005263178.6 link	c.467T>C	p.Ile156Thr	missense_variant	Exon 2 of 14		XP_005263235.1
HHIP	XM_006714288.5 link	c.467T>C	p.Ile156Thr	missense_variant	Exon 2 of 14		XP_006714351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HHIP	ENST00000296575.8 link	c.467T>C	p.Ile156Thr	missense_variant	Exon 2 of 13	1	NM_022475.3	ENSP00000296575.3		Q96QV1-1
ENSG00000285713	ENST00000649263.1 link	n.328-236814A>G		intron_variant	Intron 4 of 8			ENSP00000497507.1		A0A3B3ISY7

Frequencies

GnomAD3 genomes

AF:

0.000705

AC:

AN:

139028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00233

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000211

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000168

Gnomad OTH

AF:

0.000539

GnomAD3 exomes

AF:

0.000135

AC:

AN:

207838

Hom.:

AF XY:

0.0000878

AC XY:

AN XY:

113884

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.000263

Gnomad ASJ exome

AF:

0.00

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:

0.000858

GnomAD4 exome

AF:

0.0000426

AC:

AN:

1430422

Hom.:

Cov.:

AF XY:

0.0000464

AC XY:

AN XY:

710866

show subpopulations

Gnomad4 AFR exome

AF:

0.00139

Gnomad4 AMR exome

AF:

0.000281

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:

9.08e-7

Gnomad4 OTH exome

AF:

0.0000847

GnomAD4 genome

AF:

0.000705

AC:

AN:

139028

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

68150

show subpopulations

Gnomad4 AFR

AF:

0.00233

Gnomad4 AMR

AF:

0.000211

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000168

Gnomad4 OTH

AF:

0.000539

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.000752

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.467T>C (p.I156T) alteration is located in exon 2 (coding exon 2) of the HHIP gene. This alteration results from a T to C substitution at nucleotide position 467, causing the isoleucine (I) at amino acid position 156 to be replaced by a threonine (T). 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

0.77

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.5

N;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.023

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.16

B;P

Vest4

0.83

MVP

0.50

MPC

0.47

ClinPred

0.061

GERP RS

5.8

Varity_R

0.21

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over