4-144659714-G-A

Position:

• chr4-144659714-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022475.3(HHIP):​c.707G>A​(p.Gly236Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,609,180 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (114 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (102 hom.)
• Consequence: HHIP NM_022475.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.15

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008589804).
• BP6: Variant 4-144659714-G-A is Benign according to our data. Variant chr4-144659714-G-A is described in ClinVar as [Benign]. Clinvar id is 767978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HHIP	NM_022475.3	c.707G>A	p.Gly236Glu	missense_variant	4/13	ENST00000296575.8
HHIP	XM_005263178.6	c.707G>A	p.Gly236Glu	missense_variant	4/14
HHIP	XM_006714288.5	c.707G>A	p.Gly236Glu	missense_variant	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HHIP	ENST00000296575.8	c.707G>A	p.Gly236Glu	missense_variant	4/13	1	NM_022475.3	P1
HHIP-AS1	ENST00000512359.1	n.109C>T		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3124 AN: 152100 Hom.: 114 Cov.: 33

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00537 AC: 1327 AN: 247294 Hom.: 40 AF XY: 0.00370 AC XY: 494 AN XY: 133598

Gnomad AFR exome AF: 0.0720

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000271

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.00300

GnomAD4 exome AF: 0.00218 AC: 3174 AN: 1456962 Hom.: 102 Cov.: 30 AF XY: 0.00185 AC XY: 1343 AN XY: 724574

Gnomad4 AFR exome AF: 0.0738

Gnomad4 AMR exome AF: 0.00431

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000318

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000159

Gnomad4 OTH exome AF: 0.00537

GnomAD4 genome AF: 0.0206 AC: 3140 AN: 152218 Hom.: 114 Cov.: 33 AF XY: 0.0196 AC XY: 1460 AN XY: 74414

Gnomad4 AFR AF: 0.0711

Gnomad4 AMR AF: 0.00843

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00373 Hom.: 30

Bravo AF: 0.0236

ESP6500AA AF: 0.0731 AC: 322

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00681 AC: 827

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;D
Vest4		0.71
MVP		0.38
MPC		0.90
ClinPred		0.022	T
GERP RS		4.7
Varity_R		0.90
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs61730970; hg19: chr4-145580866;