Variant 4-144711994-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_022475.3(HHIP):c.1346C>T(p.Thr449Met) variant causes a missense change. The variant allele was found at a frequency of 0.000236 in 1,610,826 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

HHIP
NM_022475.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.62

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:

LOC124900791 (HGNC:):

LOC124900791 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0112736225).

BP6

Variant 4-144711994-C-T is Benign according to our data. Variant chr4-144711994-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 722364.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 199 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HHIP	NM_022475.3 linkuse as main transcript	c.1346C>T	p.Thr449Met	missense_variant	8/13	ENST00000296575.8
LOC124900791	XR_007058289.1 linkuse as main transcript	n.1305-7034G>A		intron_variant, non_coding_transcript_variant
HHIP	XM_005263178.6 linkuse as main transcript	c.1346C>T	p.Thr449Met	missense_variant	8/14
HHIP	XM_006714288.5 linkuse as main transcript	c.1346C>T	p.Thr449Met	missense_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HHIP	ENST00000296575.8 linkuse as main transcript	c.1346C>T	p.Thr449Met	missense_variant	8/13	1	NM_022475.3	P1	Q96QV1-1
HHIP	ENST00000512791.1 linkuse as main transcript	n.226C>T		non_coding_transcript_exon_variant	2/5	4

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

198

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00447

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

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:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000383

AC:

AN:

250940

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

135614

show subpopulations

Gnomad AFR exome

AF:

0.00554

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

181

AN:

1458636

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

725842

show subpopulations

Gnomad4 AFR exome

AF:

0.00428

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000992

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.00131

AC:

199

AN:

152190

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00448

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000243

Hom.:

Bravo

AF:

0.00136

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.014

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.53

REVEL

Benign

0.19

Sift

Uncertain

0.024

Sift4G

Benign

0.094

Polyphen

1.0

Vest4

0.60

MVP

0.26

MPC

0.75

ClinPred

0.073

GERP RS

5.7

Varity_R

0.17

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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