4-144647200-T-C

Variant names:

• chr4-144647200-T-C
• rs7689420
• NM_022475.3:c.279+246T>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.279+246T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 444,384 control chromosomes in the GnomAD database, including 144,099 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 (47704 hom., cov: 35)
  • Exomes 𝑓: 0.81 (96395 hom.)
• Consequence: HHIP NM_022475.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.427
• Publications: 56 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=-0.93).
• 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.279+246T>C		intron_variant	Intron 1 of 12	ENST00000296575.8	NP_071920.1
HHIP	XM_005263178.6	c.279+246T>C		intron_variant	Intron 1 of 13		XP_005263235.1
HHIP	XM_006714288.5	c.279+246T>C		intron_variant	Intron 1 of 13		XP_006714351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HHIP	ENST00000296575.8	c.279+246T>C		intron_variant	Intron 1 of 12	1	NM_022475.3	ENSP00000296575.3
ENSG00000285713	ENST00000649263.1	n.328-231222A>G		intron_variant	Intron 4 of 8			ENSP00000497507.1

Frequencies

GnomAD3 genomes AF: 0.789 AC: 119980 AN: 152128 Hom.: 47649 Cov.: 35

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.819

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.825

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.833

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.772

GnomAD4 exome AF: 0.807 AC: 235893 AN: 292138 Hom.: 96395 Cov.: 3 AF XY: 0.809 AC XY: 120132 AN XY: 148560

African (AFR) AF: 0.719 AC: 6576 AN: 9142

American (AMR) AF: 0.790 AC: 8066 AN: 10212

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 8413 AN: 10208

East Asian (EAS) AF: 0.585 AC: 14305 AN: 24466

South Asian (SAS) AF: 0.864 AC: 9336 AN: 10806

European-Finnish (FIN) AF: 0.835 AC: 18297 AN: 21908

Middle Eastern (MID) AF: 0.817 AC: 1172 AN: 1434

European-Non Finnish (NFE) AF: 0.837 AC: 154930 AN: 185198

Other (OTH) AF: 0.789 AC: 14798 AN: 18764

GnomAD4 genome AF: 0.789 AC: 120101 AN: 152246 Hom.: 47704 Cov.: 35 AF XY: 0.786 AC XY: 58547 AN XY: 74448

African (AFR) AF: 0.717 AC: 29780 AN: 41532

American (AMR) AF: 0.765 AC: 11698 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 2863 AN: 3472

East Asian (EAS) AF: 0.587 AC: 3035 AN: 5168

South Asian (SAS) AF: 0.872 AC: 4214 AN: 4832

European-Finnish (FIN) AF: 0.833 AC: 8833 AN: 10602

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

European-Non Finnish (NFE) AF: 0.839 AC: 57079 AN: 68022

Other (OTH) AF: 0.772 AC: 1631 AN: 2114

Alfa AF: 0.814 Hom.: 212842

Bravo AF: 0.775

Asia WGS AF: 0.717 AC: 2494 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	9.3
DANN	Benign	0.59
PhyloP100		0.43
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: rs7689420; hg19: chr4-145568352;