14-99645317-G-C

Variant names:

• chr14-99645317-G-C
• rs1276822915
• NM_001127258.3:c.110G>C

Variant summary

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

The NM_001127258.3(HHIPL1):​c.110G>C​(p.Arg37Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,303,620 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: HHIPL1 NM_001127258.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.333

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=0.10484186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHIPL1	NM_001127258.3	c.110G>C	p.Arg37Pro	missense_variant	Exon 1 of 9	ENST00000330710.10	NP_001120730.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HHIPL1	ENST00000330710.10	c.110G>C	p.Arg37Pro	missense_variant	Exon 1 of 9	1	NM_001127258.3	ENSP00000330601.5
HHIPL1	ENST00000357223.2	c.110G>C	p.Arg37Pro	missense_variant	Exon 1 of 8	1		ENSP00000349757.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1303620 Hom.: 0 Cov.: 31 AF XY: 0.00000156 AC XY: 1 AN XY: 642280

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: 9.61e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.110G>C (p.R37P) alteration is located in exon 1 (coding exon 1) of the HHIPL1 gene. This alteration results from a G to C substitution at nucleotide position 110, causing the arginine (R) at amino acid position 37 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	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.51	T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.039
Sift	Benign	0.24	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0	B;B
Vest4		0.12
MutPred		0.40		Gain of glycosylation at R37 (P = 0.0315);Gain of glycosylation at R37 (P = 0.0315);
MVP		0.16
MPC		0.60
ClinPred		0.10	T
GERP RS		2.1
Varity_R		0.18
gMVP		0.54

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: rs1276822915; hg19: chr14-100111654;