4-144659771-C-G

Variant names:

• chr4-144659771-C-G
• rs200791041
• NM_022475.3:c.764C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022475.3(HHIP):​c.764C>G​(p.Thr255Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. T255I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HHIP NM_022475.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.77
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122436345).

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.764C>G	p.Thr255Ser	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.764C>G	p.Thr255Ser	missense	Exon 4 of 13	ENSP00000296575.3	Q96QV1-1
	HHIP	ENST00000434550.2	TSL:1	c.764C>G	p.Thr255Ser	missense	Exon 4 of 4	ENSP00000408587.2	Q96QV1-2
	ENSG00000285713	ENST00000649263.1		n.328-243793G>C		intron	N/A	ENSP00000497507.1	A0A3B3ISY7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250624 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

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: 0.00000137 AC: 2 AN: 1460528 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726480

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111478

Other (OTH) AF: 0.00 AC: 0 AN: 60362

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.062
Sift	Benign	0.58	T
Sift4G	Benign	0.70	T
Polyphen		0.0020	B
Vest4		0.30
MutPred		0.46		Gain of glycosylation at T255 (P = 0.019)
MVP		0.42
MPC		0.18
ClinPred		0.14	T
GERP RS		4.9
Varity_R		0.61
gMVP		0.30
Mutation Taster		=88/12	polymorphism

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: rs200791041; hg19: chr4-145580923;