4-144659695-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_022475.3(HHIP):c.688G>A(p.Val230Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,581,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

HHIP
NM_022475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.36

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09891066).

BS2

High AC in GnomAdExome4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022475.3. 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
	HHIP	NM_022475.3	MANE Select	c.688G>A	p.Val230Ile	missense	Exon 4 of 13	NP_071920.1	Q96QV1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HHIP	ENST00000296575.8	TSL:1 MANE Select	c.688G>A	p.Val230Ile	missense	Exon 4 of 13	ENSP00000296575.3	Q96QV1-1
HHIP	ENST00000434550.2	TSL:1	c.688G>A	p.Val230Ile	missense	Exon 4 of 4	ENSP00000408587.2	Q96QV1-2
ENSG00000285713	ENST00000649263.1		n.328-243717C>T		intron	N/A	ENSP00000497507.1	A0A3B3ISY7

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000437

AC:

AN:

228700

AF XY:

0.0000646

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.000212

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1429474

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

709486

show subpopulations

African (AFR)

AF:

0.0000633

AC:

AN:

31598

American (AMR)

AF:

0.000238

AC:

AN:

37760

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24732

East Asian (EAS)

AF:

0.00

AC:

AN:

39130

South Asian (SAS)

AF:

0.0000375

AC:

AN:

80028

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1099102

Other (OTH)

AF:

0.00

AC:

AN:

58912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.000196

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.74

M_CAP

Benign

0.015

MetaRNN

Benign

0.099

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

3.4

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.64

REVEL

Benign

0.038

Sift

Benign

0.091

Sift4G

Benign

0.17

Polyphen

0.013

Vest4

0.30

MVP

0.18

MPC

0.17

ClinPred

0.038

GERP RS

2.9

Varity_R

0.16

gMVP

0.40

Mutation Taster

=91/9

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over