4-144698261-T-C

Variant names:

• chr4-144698261-T-C
• rs1492819
• NM_022475.3:c.832-8270T>C

Variant summary

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

The NM_022475.3(HHIP):​c.832-8270T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 151,980 control chromosomes in the GnomAD database, including 17,864 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 0.47 (17864 hom., cov: 32)
• Consequence: HHIP NM_022475.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.653
• Publications: 13 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHIP	NM_022475.3	c.832-8270T>C		intron_variant	Intron 4 of 12	ENST00000296575.8	NP_071920.1
LOC124900791	XR_007058289.1	n.8004A>G		non_coding_transcript_exon_variant	Exon 2 of 2
HHIP	XM_005263178.6	c.832-8270T>C		intron_variant	Intron 4 of 13		XP_005263235.1
HHIP	XM_006714288.5	c.832-8270T>C		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.832-8270T>C		intron_variant	Intron 4 of 12	1	NM_022475.3	ENSP00000296575.3
ENSG00000285713	ENST00000649263.1	n.328-282283A>G		intron_variant	Intron 4 of 8			ENSP00000497507.1
ENSG00000285783	ENST00000650526.1	n.222+56896A>G		intron_variant	Intron 2 of 14

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71356 AN: 151862 Hom.: 17847 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.502

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.451

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

GnomAD4 genome AF: 0.470 AC: 71406 AN: 151980 Hom.: 17864 Cov.: 32 AF XY: 0.476 AC XY: 35365 AN XY: 74272

African (AFR) AF: 0.291 AC: 12063 AN: 41476

American (AMR) AF: 0.534 AC: 8148 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.502 AC: 1739 AN: 3466

East Asian (EAS) AF: 0.424 AC: 2189 AN: 5158

South Asian (SAS) AF: 0.730 AC: 3522 AN: 4822

European-Finnish (FIN) AF: 0.569 AC: 6010 AN: 10560

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36180 AN: 67934

Other (OTH) AF: 0.453 AC: 956 AN: 2112

Alfa AF: 0.508 Hom.: 29797

Bravo AF: 0.453

Asia WGS AF: 0.563 AC: 1954 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.8
DANN	Benign	0.73
PhyloP100		0.65
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: rs1492819; hg19: chr4-145619413;