chr2-219054784-C-T

Variant names:

• chr2-219054784-C-T
• rs956439051
• NM_002181.4:c.*423G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_002181.4(IHH):​c.*423G>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 0.0000612 in 212,406 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: IHH NM_002181.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.295
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• acrocapitofemoral dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000722 (11/152296) while in subpopulation AFR AF = 0.00012 (5/41576). AF 95% confidence interval is 0.0000473. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IHH	NM_002181.4	MANE Select	c.*423G>A		3_prime_UTR	Exon 3 of 3	NP_002172.2	Q14623

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IHH	ENST00000295731.7	TSL:1 MANE Select	c.*423G>A		3_prime_UTR	Exon 3 of 3	ENSP00000295731.5	Q14623

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000333 AC: 2 AN: 60110 Hom.: 0 Cov.: 0 AF XY: 0.0000325 AC XY: 1 AN XY: 30764

African (AFR) AF: 0.00 AC: 0 AN: 1452

American (AMR) AF: 0.00 AC: 0 AN: 3594

Ashkenazi Jewish (ASJ) AF: 0.000705 AC: 1 AN: 1418

East Asian (EAS) AF: 0.00 AC: 0 AN: 2536

South Asian (SAS) AF: 0.00 AC: 0 AN: 7654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 250

European-Non Finnish (NFE) AF: 0.0000274 AC: 1 AN: 36452

Other (OTH) AF: 0.00 AC: 0 AN: 3370

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74472

African (AFR) AF: 0.000120 AC: 5 AN: 41576

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Brachydactyly type A1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.47
DANN	Benign	0.77
PhyloP100		-0.29

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: rs956439051; hg19: chr2-219919506;