4-144655406-G-A

Position:

• chr4-144655406-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000296575.8(HHIP):​c.472+2609G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 151,950 control chromosomes in the GnomAD database, including 11,466 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 0.37 (11466 hom., cov: 32)
• Consequence: HHIP ENST00000296575.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.445

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]

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

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HHIP	NM_022475.3	c.472+2609G>A		intron_variant		ENST00000296575.8	NP_071920.1
HHIP	XM_005263178.6	c.472+2609G>A		intron_variant			XP_005263235.1
HHIP	XM_006714288.5	c.472+2609G>A		intron_variant			XP_006714351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HHIP	ENST00000296575.8	c.472+2609G>A		intron_variant		1	NM_022475.3	ENSP00000296575	P1
HHIP-AS1	ENST00000512359.1	n.209-2630C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.369 AC: 55957 AN: 151832 Hom.: 11467 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.373

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

GnomAD4 genome AF: 0.368 AC: 55973 AN: 151950 Hom.: 11466 Cov.: 32 AF XY: 0.372 AC XY: 27638 AN XY: 74248

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.452

Gnomad4 EAS AF: 0.216

Gnomad4 SAS AF: 0.519

Gnomad4 FIN AF: 0.469

Gnomad4 NFE AF: 0.452

Gnomad4 OTH AF: 0.368

Alfa AF: 0.420 Hom.: 6172

Bravo AF: 0.354

Asia WGS AF: 0.319 AC: 1110 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.35
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs2220514; hg19: chr4-145576558;