4-144666964-A-T

Variant names:

• chr4-144666964-A-T
• rs6537302
• NM_022475.3:c.831+7126A>T

Variant summary

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

The NM_022475.3(HHIP):​c.831+7126A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 152,086 control chromosomes in the GnomAD database, including 11,325 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 0.36 (11325 hom., cov: 32)
• Consequence: HHIP NM_022475.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0570
• Publications: 8 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHIP	NM_022475.3	c.831+7126A>T		intron_variant	Intron 4 of 12	ENST00000296575.8	NP_071920.1
HHIP	XM_005263178.6	c.831+7126A>T		intron_variant	Intron 4 of 13		XP_005263235.1
HHIP	XM_006714288.5	c.831+7126A>T		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.831+7126A>T		intron_variant	Intron 4 of 12	1	NM_022475.3	ENSP00000296575.3
ENSG00000285713	ENST00000649263.1	n.328-250986T>A		intron_variant	Intron 4 of 8			ENSP00000497507.1
HHIP	ENST00000509630.1	n.498+7126A>T		intron_variant	Intron 3 of 3	4
ENSG00000285783	ENST00000650526.1	n.222+88193T>A		intron_variant	Intron 2 of 14

Frequencies

GnomAD3 genomes AF: 0.362 AC: 55004 AN: 151968 Hom.: 11327 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.369

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

GnomAD4 genome AF: 0.362 AC: 55020 AN: 152086 Hom.: 11325 Cov.: 32 AF XY: 0.367 AC XY: 27252 AN XY: 74342

African (AFR) AF: 0.155 AC: 6424 AN: 41498

American (AMR) AF: 0.411 AC: 6285 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1577 AN: 3468

East Asian (EAS) AF: 0.215 AC: 1112 AN: 5180

South Asian (SAS) AF: 0.523 AC: 2512 AN: 4804

European-Finnish (FIN) AF: 0.475 AC: 5019 AN: 10558

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.452 AC: 30739 AN: 67986

Other (OTH) AF: 0.364 AC: 769 AN: 2112

Alfa AF: 0.409 Hom.: 1665

Bravo AF: 0.346

Asia WGS AF: 0.318 AC: 1105 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.3
DANN	Benign	0.48
PhyloP100		0.057
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: rs6537302; hg19: chr4-145588116;