rs978591672

Variant names:

• chr14-99645253-G-C
• rs978591672
• NM_001127258.3:c.46G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-99645253-G-C
• chr14-99645253-G-A
• chr14-99645253-G-T

Variant summary

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

The NM_001127258.3(HHIPL1):​c.46G>C​(p.Gly16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000362 in 1,381,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: HHIPL1 NM_001127258.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0140
• Publications: 0 publications found

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

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=0.068660915).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127258.3. 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
	HHIPL1	NM_001127258.3	MANE Select	c.46G>C	p.Gly16Arg	missense	Exon 1 of 9	NP_001120730.1	F1T0G3
	HHIPL1	NM_032425.5		c.46G>C	p.Gly16Arg	missense	Exon 1 of 8	NP_115801.3	Q96JK4-2
	HHIPL1	NM_001329411.2		c.61-6971G>C		intron	N/A	NP_001316340.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HHIPL1	ENST00000330710.10	TSL:1 MANE Select	c.46G>C	p.Gly16Arg	missense	Exon 1 of 9	ENSP00000330601.5	Q96JK4-1
	HHIPL1	ENST00000357223.2	TSL:1	c.46G>C	p.Gly16Arg	missense	Exon 1 of 8	ENSP00000349757.2	Q96JK4-2
	HHIPL1	ENST00000949017.1		c.46G>C	p.Gly16Arg	missense	Exon 1 of 9	ENSP00000619076.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152100 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000244 AC: 3 AN: 1229858 Hom.: 0 Cov.: 31 AF XY: 0.00000167 AC XY: 1 AN XY: 600528

African (AFR) AF: 0.00 AC: 0 AN: 24704

American (AMR) AF: 0.00 AC: 0 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18744

East Asian (EAS) AF: 0.00 AC: 0 AN: 27154

South Asian (SAS) AF: 0.0000179 AC: 1 AN: 55922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3488

European-Non Finnish (NFE) AF: 0.00000199 AC: 2 AN: 1003714

Other (OTH) AF: 0.00 AC: 0 AN: 50286

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152100 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74306

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

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000540 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	16
DANN	Benign	0.68
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.014
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.036
Sift	Benign	0.56	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.097
MutPred		0.62		Gain of MoRF binding (P = 0.005)
MVP		0.088
MPC		0.49
ClinPred		0.074	T
GERP RS		-1.7
PromoterAI		0.015	Neutral
Varity_R		0.066
gMVP		0.30
Mutation Taster		=91/9	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: rs978591672; hg19: chr14-100111590;