4-144715580-T-C

Position:

• chr4-144715580-T-C

Variant summary

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

The NM_022475.3(HHIP):​c.1678+150T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 622,800 control chromosomes in the GnomAD database, including 109,706 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 0.57 (25123 hom., cov: 33)
  • Exomes 𝑓: 0.60 (84583 hom.)
• Consequence: HHIP NM_022475.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117

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]

LOC124900791 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HHIP	NM_022475.3	c.1678+150T>C		intron_variant		ENST00000296575.8	NP_071920.1
LOC124900791	XR_007058289.1	n.1305-10620A>G		intron_variant, non_coding_transcript_variant
HHIP	XM_005263178.6	c.1678+150T>C		intron_variant			XP_005263235.1
HHIP	XM_006714288.5	c.1678+150T>C		intron_variant			XP_006714351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HHIP	ENST00000296575.8	c.1678+150T>C		intron_variant		1	NM_022475.3	ENSP00000296575	P1
HHIP	ENST00000512791.1	n.781T>C		non_coding_transcript_exon_variant	5/5	4

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86949 AN: 151924 Hom.: 25074 Cov.: 33

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.548

GnomAD4 exome AF: 0.599 AC: 281818 AN: 470758 Hom.: 84583 Cov.: 7 AF XY: 0.602 AC XY: 146107 AN XY: 242526

Gnomad4 AFR exome AF: 0.541

Gnomad4 AMR exome AF: 0.665

Gnomad4 ASJ exome AF: 0.579

Gnomad4 EAS exome AF: 0.457

Gnomad4 SAS exome AF: 0.770

Gnomad4 FIN exome AF: 0.647

Gnomad4 NFE exome AF: 0.592

Gnomad4 OTH exome AF: 0.586

GnomAD4 genome AF: 0.573 AC: 87060 AN: 152042 Hom.: 25123 Cov.: 33 AF XY: 0.575 AC XY: 42728 AN XY: 74310

Gnomad4 AFR AF: 0.525

Gnomad4 AMR AF: 0.582

Gnomad4 ASJ AF: 0.573

Gnomad4 EAS AF: 0.425

Gnomad4 SAS AF: 0.757

Gnomad4 FIN AF: 0.636

Gnomad4 NFE AF: 0.588

Gnomad4 OTH AF: 0.549

Alfa AF: 0.577 Hom.: 10532

Bravo AF: 0.560

Asia WGS AF: 0.589 AC: 2045 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	0.70
DANN	Benign	0.47

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: rs6537310; hg19: chr4-145636732; COSMIC: COSV56845414;