4-144653692-A-G

Variant names:

• chr4-144653692-A-G
• rs1812175
• NM_022475.3:c.472+895A>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.472+895A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 151,962 control chromosomes in the GnomAD database, including 47,656 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 0.79 (47656 hom., cov: 30)
• Consequence: HHIP NM_022475.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.271
• Publications: 57 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:):

HHIP-AS1 (HGNC:44182): (HHIP antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHIP	NM_022475.3	c.472+895A>G		intron_variant	Intron 2 of 12	ENST00000296575.8	NP_071920.1
HHIP	XM_005263178.6	c.472+895A>G		intron_variant	Intron 2 of 13		XP_005263235.1
HHIP	XM_006714288.5	c.472+895A>G		intron_variant	Intron 2 of 13		XP_006714351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HHIP	ENST00000296575.8	c.472+895A>G		intron_variant	Intron 2 of 12	1	NM_022475.3	ENSP00000296575.3
ENSG00000285713	ENST00000649263.1	n.328-237714T>C		intron_variant	Intron 4 of 8			ENSP00000497507.1

Frequencies

GnomAD3 genomes AF: 0.789 AC: 119820 AN: 151844 Hom.: 47601 Cov.: 30

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.819

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.824

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.833

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.771

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

GnomAD4 genome AF: 0.789 AC: 119941 AN: 151962 Hom.: 47656 Cov.: 30 AF XY: 0.787 AC XY: 58432 AN XY: 74272

African (AFR) AF: 0.719 AC: 29766 AN: 41426

American (AMR) AF: 0.764 AC: 11665 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 2857 AN: 3466

East Asian (EAS) AF: 0.589 AC: 3031 AN: 5150

South Asian (SAS) AF: 0.872 AC: 4191 AN: 4808

European-Finnish (FIN) AF: 0.833 AC: 8803 AN: 10570

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.839 AC: 57028 AN: 67960

Other (OTH) AF: 0.771 AC: 1630 AN: 2114

Alfa AF: 0.819 Hom.: 195947

Bravo AF: 0.775

Asia WGS AF: 0.716 AC: 2487 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.7
DANN	Benign	0.46
PhyloP100		-0.27
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: rs1812175; hg19: chr4-145574844;