Variant chr4-144658801-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_022475.3(HHIP):c.484A>G(p.Thr162Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00012 in 1,611,598 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

HHIP
NM_022475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.86

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:

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12160963).

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HHIP	NM_022475.3 linkuse as main transcript	c.484A>G	p.Thr162Ala	missense_variant	3/13	ENST00000296575.8
HHIP	XM_005263178.6 linkuse as main transcript	c.484A>G	p.Thr162Ala	missense_variant	3/14
HHIP	XM_006714288.5 linkuse as main transcript	c.484A>G	p.Thr162Ala	missense_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HHIP	ENST00000296575.8 linkuse as main transcript	c.484A>G	p.Thr162Ala	missense_variant	3/13	1	NM_022475.3	P1	Q96QV1-1
HHIP-AS1	ENST00000512359.1 linkuse as main transcript	n.208+814T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000960

AC:

AN:

249990

Hom.:

AF XY:

0.0000888

AC XY:

AN XY:

135112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.0000998

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000115

AC:

168

AN:

1459452

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

726012

show subpopulations

Gnomad4 AFR exome

AF:

0.0000900

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000106

Gnomad4 OTH exome

AF:

0.000183

GnomAD4 genome

AF:

0.000171

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000163

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

The c.484A>G (p.T162A) alteration is located in exon 3 (coding exon 3) of the HHIP gene. This alteration results from a A to G substitution at nucleotide position 484, causing the threonine (T) at amino acid position 162 to be replaced by an alanine (A). 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

Benign

0.098

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.027

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.60

N;N

REVEL

Benign

0.26

Sift

Benign

0.52

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.0

B;B

Vest4

0.26

MVP

0.64

MPC

0.20

ClinPred

0.091

GERP RS

5.9

Varity_R

0.092

gMVP

0.60

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