2-219055032-G-C

Variant names:

• chr2-219055032-G-C
• rs3099
• NM_002181.4:c.*175C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002181.4(IHH):​c.*175C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 682,856 control chromosomes in the GnomAD database, including 128,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (23395 hom., cov: 33)
  • Exomes 𝑓: 0.62 (104880 hom.)
• Consequence: IHH NM_002181.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.481
• Publications: 14 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-219055032-G-C is Benign according to our data. Variant chr2-219055032-G-C is described in ClinVar as Benign. ClinVar VariationId is 334429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IHH	NM_002181.4	c.*175C>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000295731.7	NP_002172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IHH	ENST00000295731.7	c.*175C>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_002181.4	ENSP00000295731.5

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79355 AN: 152024 Hom.: 23399 Cov.: 33

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.737

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.510

GnomAD4 exome AF: 0.616 AC: 327039 AN: 530714 Hom.: 104880 Cov.: 6 AF XY: 0.615 AC XY: 169551 AN XY: 275736

African (AFR) AF: 0.249 AC: 3486 AN: 14002

American (AMR) AF: 0.509 AC: 10595 AN: 20806

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 8967 AN: 14420

East Asian (EAS) AF: 0.293 AC: 9177 AN: 31368

South Asian (SAS) AF: 0.553 AC: 26422 AN: 47774

European-Finnish (FIN) AF: 0.736 AC: 29049 AN: 39492

Middle Eastern (MID) AF: 0.572 AC: 1250 AN: 2184

European-Non Finnish (NFE) AF: 0.667 AC: 221393 AN: 332116

Other (OTH) AF: 0.585 AC: 16700 AN: 28552

GnomAD4 genome AF: 0.522 AC: 79355 AN: 152142 Hom.: 23395 Cov.: 33 AF XY: 0.525 AC XY: 39019 AN XY: 74380

African (AFR) AF: 0.254 AC: 10528 AN: 41526

American (AMR) AF: 0.510 AC: 7793 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2126 AN: 3470

East Asian (EAS) AF: 0.301 AC: 1553 AN: 5154

South Asian (SAS) AF: 0.540 AC: 2604 AN: 4824

European-Finnish (FIN) AF: 0.737 AC: 7808 AN: 10590

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45235 AN: 67976

Other (OTH) AF: 0.505 AC: 1065 AN: 2110

Alfa AF: 0.485 Hom.: 1669

Bravo AF: 0.490

Asia WGS AF: 0.330 AC: 1151 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 10, 2019

GeneDx

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.3
DANN	Benign	0.67
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3099; hg19: chr2-219919754;