rs2306924

Positions:

• chr4-144661384-A-G
• chr4-144661384-A-T

Variant summary

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

The NM_022475.3(HHIP):​c.831+1546A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 152,020 control chromosomes in the GnomAD database, including 24,487 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 0.56 (24487 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: HHIP NM_022475.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.181

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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HHIP	NM_022475.3	c.831+1546A>G		intron_variant		ENST00000296575.8	NP_071920.1
HHIP	XM_005263178.6	c.831+1546A>G		intron_variant			XP_005263235.1
HHIP	XM_006714288.5	c.831+1546A>G		intron_variant			XP_006714351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HHIP	ENST00000296575.8	c.831+1546A>G		intron_variant		1	NM_022475.3	ENSP00000296575	P1
HHIP	ENST00000509630.1	n.498+1546A>G		intron_variant, non_coding_transcript_variant		4
HHIP-AS1	ENST00000512359.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85516 AN: 151902 Hom.: 24432 Cov.: 32

Gnomad AFR AF: 0.659

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.525

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.563 AC: 85638 AN: 152020 Hom.: 24487 Cov.: 32 AF XY: 0.565 AC XY: 41985 AN XY: 74300

Gnomad4 AFR AF: 0.660

Gnomad4 AMR AF: 0.558

Gnomad4 ASJ AF: 0.542

Gnomad4 EAS AF: 0.425

Gnomad4 SAS AF: 0.734

Gnomad4 FIN AF: 0.542

Gnomad4 NFE AF: 0.510

Gnomad4 OTH AF: 0.526

Alfa AF: 0.528 Hom.: 34078

Bravo AF: 0.561

Asia WGS AF: 0.579 AC: 2013 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.5
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2306924; hg19: chr4-145582536;