14-99645226-G-A

Position:

• chr14-99645226-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127258.3(HHIPL1):​c.19G>A​(p.Gly7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000171 in 1,172,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: HHIPL1 NM_001127258.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.264

Genes affected

HHIPL1 (HGNC:19710): (HHIP like 1) This gene encodes a protein that belongs to the glucose/sorbosone dehydrogenase family. The encoded protein also contains a domain that binds folate and reduced folic acid derivatives. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18487623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HHIPL1	NM_001127258.3	c.19G>A	p.Gly7Arg	missense_variant	1/9	ENST00000330710.10	NP_001120730.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HHIPL1	ENST00000330710.10	c.19G>A	p.Gly7Arg	missense_variant	1/9	1	NM_001127258.3	ENSP00000330601.5
HHIPL1	ENST00000357223.2	c.19G>A	p.Gly7Arg	missense_variant	1/8	1		ENSP00000349757.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000171 AC: 2 AN: 1172012 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 566126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000103

Gnomad4 OTH exome AF: 0.0000211

GnomAD4 genome Cov.: 34

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

May 15, 2024

The c.19G>A (p.G7R) alteration is located in exon 1 (coding exon 1) of the HHIPL1 gene. This alteration results from a G to A substitution at nucleotide position 19, causing the glycine (G) at amino acid position 7 to be replaced by an arginine (R). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.57	N;N
REVEL	Benign	0.066
Sift	Uncertain	0.021	D;T
Sift4G	Benign	0.14	T;T
Polyphen		0.97	D;D
Vest4		0.25
MutPred		0.40		Gain of methylation at G7 (P = 0.0024);Gain of methylation at G7 (P = 0.0024);
MVP		0.33
MPC		0.49
ClinPred		0.64	D
GERP RS		2.2
Varity_R		0.14
gMVP		0.47

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: rs1354072292; hg19: chr14-100111563;