2-219055032-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_002181.4(IHH):​c.*175C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 683,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: IHH NM_002181.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000789 (12/152074) while in subpopulation AFR AF = 0.000266 (11/41416). AF 95% confidence interval is 0.000149. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.*175C>A		3_prime_UTR	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.*175C>A		3_prime_UTR	Exon 3 of 3	ENSP00000295731.5

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152074 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.0000245 AC: 13 AN: 531372 Hom.: 0 Cov.: 6 AF XY: 0.0000181 AC XY: 5 AN XY: 276064

African (AFR) AF: 0.000286 AC: 4 AN: 14004

American (AMR) AF: 0.00 AC: 0 AN: 20830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14428

East Asian (EAS) AF: 0.0000319 AC: 1 AN: 31390

South Asian (SAS) AF: 0.0000418 AC: 2 AN: 47816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2188

European-Non Finnish (NFE) AF: 0.0000120 AC: 4 AN: 332586

Other (OTH) AF: 0.0000700 AC: 2 AN: 28584

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152074 Hom.: 0 Cov.: 33 AF XY: 0.0000808 AC XY: 6 AN XY: 74280

African (AFR) AF: 0.000266 AC: 11 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000101 Hom.: 1669

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.2
DANN	Benign	0.78
PhyloP100		0.48

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;