4-144715580-T-C

Variant names:

• chr4-144715580-T-C
• rs6537310
• NM_022475.3:c.1678+150T>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.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
• Publications: 7 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 = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHIP	NM_022475.3	c.1678+150T>C		intron_variant	Intron 10 of 12	ENST00000296575.8	NP_071920.1
HHIP	XM_005263178.6	c.1678+150T>C		intron_variant	Intron 10 of 13		XP_005263235.1
HHIP	XM_006714288.5	c.1678+150T>C		intron_variant	Intron 10 of 13		XP_006714351.1
LOC124900791	XR_007058289.1	n.1305-10620A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HHIP	ENST00000296575.8	c.1678+150T>C		intron_variant	Intron 10 of 12	1	NM_022475.3	ENSP00000296575.3
ENSG00000285713	ENST00000649263.1	n.328-299602A>G		intron_variant	Intron 4 of 8			ENSP00000497507.1
HHIP	ENST00000512791.1	n.781T>C		non_coding_transcript_exon_variant	Exon 5 of 5	4
ENSG00000285783	ENST00000650526.1	n.222+39577A>G		intron_variant	Intron 2 of 14

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

African (AFR) AF: 0.541 AC: 6934 AN: 12824

American (AMR) AF: 0.665 AC: 11309 AN: 17016

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 6799 AN: 11750

East Asian (EAS) AF: 0.457 AC: 13011 AN: 28440

South Asian (SAS) AF: 0.770 AC: 22065 AN: 28660

European-Finnish (FIN) AF: 0.647 AC: 17522 AN: 27092

Middle Eastern (MID) AF: 0.594 AC: 1053 AN: 1772

European-Non Finnish (NFE) AF: 0.592 AC: 188758 AN: 318698

Other (OTH) AF: 0.586 AC: 14367 AN: 24506

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

African (AFR) AF: 0.525 AC: 21775 AN: 41470

American (AMR) AF: 0.582 AC: 8887 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1989 AN: 3472

East Asian (EAS) AF: 0.425 AC: 2199 AN: 5174

South Asian (SAS) AF: 0.757 AC: 3646 AN: 4816

European-Finnish (FIN) AF: 0.636 AC: 6721 AN: 10562

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.588 AC: 39983 AN: 67970

Other (OTH) AF: 0.549 AC: 1158 AN: 2110

Alfa AF: 0.578 Hom.: 11837

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
PhyloP100		-0.12
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: rs6537310; hg19: chr4-145636732; COSMIC: COSV56845414;