rs3731881

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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

Publications

25 publications found

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 Gene-Disease associations (from GenCC):

brachydactyly type A1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
acrocapitofemoral dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet

IHH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 334440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002181.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IHH	NM_002181.4	MANE Select	c.753T>C	p.Pro251Pro	synonymous	Exon 3 of 3	NP_002172.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IHH	ENST00000295731.7	TSL:1 MANE Select	c.753T>C	p.Pro251Pro	synonymous	Exon 3 of 3	ENSP00000295731.5

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

GnomAD2 exomes

AF:

0.596

AC:

149572

AN:

250806

AF XY:

0.604

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 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

African (AFR)

AF:

0.450

AC:

15082

AN:

33480

American (AMR)

AF:

0.510

AC:

22802

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.634

AC:

16575

AN:

26130

East Asian (EAS)

AF:

0.296

AC:

11755

AN:

39686

South Asian (SAS)

AF:

0.559

AC:

48234

AN:

86256

European-Finnish (FIN)

AF:

0.735

AC:

39135

AN:

53274

Middle Eastern (MID)

AF:

0.566

AC:

3265

AN:

5766

European-Non Finnish (NFE)

AF:

0.667

AC:

741579

AN:

1111926

Other (OTH)

AF:

0.609

AC:

36779

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

23901

47802

71703

95604

119505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19010

38020

57030

76040

95050

<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:

0.582

AC:

88555

AN:

152152

Hom.:

26809

Cov.:

AF XY:

0.583

AC XY:

43341

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.460

AC:

19099

AN:

41500

American (AMR)

AF:

0.536

AC:

8200

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.625

AC:

2168

AN:

3470

East Asian (EAS)

AF:

0.301

AC:

1558

AN:

5174

South Asian (SAS)

AF:

0.542

AC:

2614

AN:

4826

European-Finnish (FIN)

AF:

0.737

AC:

7814

AN:

10598

Middle Eastern (MID)

AF:

0.575

AC:

169

AN:

294

European-Non Finnish (NFE)

AF:

0.666

AC:

45284

AN:

67974

Other (OTH)

AF:

0.555

AC:

1170

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1906

3813

5719

7626

9532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

744

1488

2232

2976

3720

<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:

0.626

Hom.:

73810

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 27, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 02, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 12525541, 14651602)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Acrocapitofemoral dysplasia

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Brachydactyly type A1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.3

(source)

DANN

Benign

0.60

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over