rs3731881

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002181.4(IHH):c.753T>C(p.Pro251Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,613,762 control chromosomes in the GnomAD database, including 330,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 26809 hom., cov: 34)

Exomes 𝑓: 0.64 ( 304115 hom. )

Consequence

IHH
NM_002181.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.12

Variant links:

Genes affected

IHH (HGNC:5956): (Indian hedgehog signaling molecule) This gene encodes a member of the hedgehog family of proteins. The encoded preproprotein is proteolytically processed to generate multiple protein products, including an N-terminal fragment that is involved in signaling. Hedgehog family proteins are essential secreted signaling molecules that regulate a variety of developmental processes including growth, patterning and morphogenesis. The protein encoded by this gene specifically plays a role in bone growth and differentiation. Mutations in this gene are the cause of brachydactyly type A1, which is characterized by shortening or malformation of the fingers and toes. Mutations in this gene are also the cause of acrocapitofemoral dysplasia. [provided by RefSeq, Nov 2015]

IHH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-219055690-A-G is Benign according to our data. Variant chr2-219055690-A-G is described in ClinVar as [Benign]. Clinvar id is 334440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219055690-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.12 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IHH	NM_002181.4 linkuse as main transcript	c.753T>C	p.Pro251Pro	synonymous_variant	3/3	ENST00000295731.7	NP_002172.2	Q14623

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IHH	ENST00000295731.7 linkuse as main transcript	c.753T>C	p.Pro251Pro	synonymous_variant	3/3	1	NM_002181.4	ENSP00000295731.5		Q14623

Frequencies

GnomAD3 genomes

AF:

0.582

AC:

88538

AN:

152034

Hom.:

26812

Cov.:

show subpopulations

Gnomad AFR

AF:

0.461

Gnomad AMI

AF:

0.525

Gnomad AMR

AF:

0.536

Gnomad ASJ

AF:

0.625

Gnomad EAS

AF:

0.301

Gnomad SAS

AF:

0.541

Gnomad FIN

AF:

0.737

Gnomad MID

AF:

0.595

Gnomad NFE

AF:

0.666

Gnomad OTH

AF:

0.560

GnomAD3 exomes

AF:

0.596

AC:

149572

AN:

250806

Hom.:

46269

AF XY:

0.604

AC XY:

81955

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.455

Gnomad AMR exome

AF:

0.510

Gnomad ASJ exome

AF:

0.632

Gnomad EAS exome

AF:

0.312

Gnomad SAS exome

AF:

0.556

Gnomad FIN exome

AF:

0.742

Gnomad NFE exome

AF:

0.669

Gnomad OTH exome

AF:

0.595

GnomAD4 exome

AF:

0.640

AC:

935206

AN:

1461610

Hom.:

304115

Cov.:

AF XY:

0.638

AC XY:

464204

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.450

Gnomad4 AMR exome

AF:

0.510

Gnomad4 ASJ exome

AF:

0.634

Gnomad4 EAS exome

AF:

0.296

Gnomad4 SAS exome

AF:

0.559

Gnomad4 FIN exome

AF:

0.735

Gnomad4 NFE exome

AF:

0.667

Gnomad4 OTH exome

AF:

0.609

GnomAD4 genome

AF:

0.582

AC:

88555

AN:

152152

Hom.:

26809

Cov.:

AF XY:

0.583

AC XY:

43341

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.460

Gnomad4 AMR

AF:

0.536

Gnomad4 ASJ

AF:

0.625

Gnomad4 EAS

AF:

0.301

Gnomad4 SAS

AF:

0.542

Gnomad4 FIN

AF:

0.737

Gnomad4 NFE

AF:

0.666

Gnomad4 OTH

AF:

0.555

Alfa

AF:

0.635

Hom.:

50650

Bravo

AF:

0.557

Asia WGS

AF:

0.340

AC:

1186

AN:

3478

EpiCase

AF:

0.652

EpiControl

AF:

0.657

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 27, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2018	This variant is associated with the following publications: (PMID: 12525541, 14651602) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Acrocapitofemoral dysplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Brachydactyly type A1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.3

DANN

Benign

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