4-144646851-T-C

Position:

• chr4-144646851-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_022475.3(HHIP):​c.176T>C​(p.Leu59Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: HHIP NM_022475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07374826).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HHIP	NM_022475.3	c.176T>C	p.Leu59Pro	missense_variant	1/13	ENST00000296575.8
HHIP	XM_005263178.6	c.176T>C	p.Leu59Pro	missense_variant	1/14
HHIP	XM_006714288.5	c.176T>C	p.Leu59Pro	missense_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HHIP	ENST00000296575.8	c.176T>C	p.Leu59Pro	missense_variant	1/13	1	NM_022475.3	P1
HHIP-AS1	ENST00000512359.1	n.284-3117A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.176T>C (p.L59P) alteration is located in exon 1 (coding exon 1) of the HHIP gene. This alteration results from a T to C substitution at nucleotide position 176, causing the leucine (L) at amino acid position 59 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.090	T;.
Eigen	Benign	0.0097
Eigen_PC	Benign	0.048
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.080	N;N
REVEL	Benign	0.057
Sift	Benign	0.031	D;D
Sift4G	Benign	0.16	T;D
Polyphen		0.99	D;B
Vest4		0.16
MutPred		0.33		Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);
MVP		0.21
MPC		0.33
ClinPred		0.58	D
GERP RS		2.6
Varity_R		0.44
gMVP		0.81

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: rs1578670476; hg19: chr4-145568003;