rs2575580

Variant names:

• chr4-144683873-A-G
• rs2575580
• NM_022475.3:c.832-22658A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022475.3(HHIP):​c.832-22658A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 152,022 control chromosomes in the GnomAD database, including 805 homozygotes. 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 0.091 (805 hom., cov: 31)
• Consequence: HHIP NM_022475.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0240
• Publications: 10 publications found

Genes affected

HHIP (HGNC:14866): (hedgehog interacting protein) This gene encodes a member of the hedgehog-interacting protein (HHIP) family. The hedgehog (HH) proteins are evolutionarily conserved protein, which are important morphogens for a wide range of developmental processes, including anteroposterior patterns of limbs and regulation of left-right asymmetry in embryonic development. Multiple cell-surface receptors are responsible for transducing and/or regulating HH signals. The HHIP encoded by this gene is a highly conserved, vertebrate-specific inhibitor of HH signaling. It interacts with all three HH family members, SHH, IHH and DHH. Two single nucleotide polymorphisms (SNPs) near this gene are significantly associated with risk of chronic obstructive pulmonary disease (COPD). A single nucleotide polymorphism in this gene is also strongly associated with human height.[provided by RefSeq, Feb 2011]

ENSG00000285713 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHIP	NM_022475.3	c.832-22658A>G		intron_variant	Intron 4 of 12	ENST00000296575.8	NP_071920.1
HHIP	XM_005263178.6	c.832-22658A>G		intron_variant	Intron 4 of 13		XP_005263235.1
HHIP	XM_006714288.5	c.832-22658A>G		intron_variant	Intron 4 of 13		XP_006714351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HHIP	ENST00000296575.8	c.832-22658A>G		intron_variant	Intron 4 of 12	1	NM_022475.3	ENSP00000296575.3
ENSG00000285713	ENST00000649263.1	n.328-267895T>C		intron_variant	Intron 4 of 8			ENSP00000497507.1
HHIP	ENST00000509630.1	n.499-1728A>G		intron_variant	Intron 3 of 3	4
ENSG00000285783	ENST00000650526.1	n.222+71284T>C		intron_variant	Intron 2 of 14

Frequencies

GnomAD3 genomes AF: 0.0909 AC: 13802 AN: 151904 Hom.: 806 Cov.: 31

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0261

Gnomad SAS AF: 0.0613

Gnomad FIN AF: 0.0903

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.114

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0908 AC: 13799 AN: 152022 Hom.: 805 Cov.: 31 AF XY: 0.0896 AC XY: 6661 AN XY: 74310

African (AFR) AF: 0.0287 AC: 1191 AN: 41488

American (AMR) AF: 0.113 AC: 1732 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 366 AN: 3468

East Asian (EAS) AF: 0.0258 AC: 133 AN: 5160

South Asian (SAS) AF: 0.0616 AC: 296 AN: 4806

European-Finnish (FIN) AF: 0.0903 AC: 955 AN: 10578

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8642 AN: 67950

Other (OTH) AF: 0.112 AC: 236 AN: 2104

Alfa AF: 0.113 Hom.: 1798

Bravo AF: 0.0931

Asia WGS AF: 0.0490 AC: 173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.6
DANN	Benign	0.68
PhyloP100		0.024
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: rs2575580; hg19: chr4-145605025;