4-144659695-G-T

Variant names:

• chr4-144659695-G-T
• rs147080443
• NM_022475.3:c.688G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022475.3(HHIP):​c.688G>T​(p.Val230Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V230I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: HHIP NM_022475.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36
• Publications: 1 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:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HHIP	NM_022475.3	MANE Select	c.688G>T	p.Val230Phe	missense	Exon 4 of 13	NP_071920.1	Q96QV1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HHIP	ENST00000296575.8	TSL:1 MANE Select	c.688G>T	p.Val230Phe	missense	Exon 4 of 13	ENSP00000296575.3	Q96QV1-1
	HHIP	ENST00000434550.2	TSL:1	c.688G>T	p.Val230Phe	missense	Exon 4 of 4	ENSP00000408587.2	Q96QV1-2
	ENSG00000285713	ENST00000649263.1		n.328-243717C>A		intron	N/A	ENSP00000497507.1	A0A3B3ISY7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228700 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000115

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429474 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 709486

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 37760

Ashkenazi Jewish (ASJ) AF: 0.0000404 AC: 1 AN: 24732

East Asian (EAS) AF: 0.00 AC: 0 AN: 39130

South Asian (SAS) AF: 0.00 AC: 0 AN: 80028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099102

Other (OTH) AF: 0.00 AC: 0 AN: 58912

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.4
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.68		Loss of sheet (P = 0.0315)
MVP		0.50
MPC		0.55
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.93
gMVP		0.86
Mutation Taster		=12/88	disease causing

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: rs147080443; hg19: chr4-145580847;