14-99645329-A-G

Variant names:

• chr14-99645329-A-G
• rs776085652
• NM_001127258.3:c.122A>G

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.122A>G​(p.Gln41Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,010 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q41L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HHIPL1 NM_001127258.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.49
• 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=0.2522395).

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.122A>G	p.Gln41Arg	missense	Exon 1 of 9	NP_001120730.1	F1T0G3
	HHIPL1	NM_032425.5		c.122A>G	p.Gln41Arg	missense	Exon 1 of 8	NP_115801.3	Q96JK4-2
	HHIPL1	NM_001329411.2		c.61-6895A>G		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.122A>G	p.Gln41Arg	missense	Exon 1 of 9	ENSP00000330601.5	Q96JK4-1
	HHIPL1	ENST00000357223.2	TSL:1	c.122A>G	p.Gln41Arg	missense	Exon 1 of 8	ENSP00000349757.2	Q96JK4-2
	HHIPL1	ENST00000949017.1		c.122A>G	p.Gln41Arg	missense	Exon 1 of 9	ENSP00000619076.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152010 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1307210 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 644196

African (AFR) AF: 0.00 AC: 0 AN: 26498

American (AMR) AF: 0.00 AC: 0 AN: 24496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22784

East Asian (EAS) AF: 0.00 AC: 0 AN: 27826

South Asian (SAS) AF: 0.00 AC: 0 AN: 70610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3820

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1042524

Other (OTH) AF: 0.00 AC: 0 AN: 53868

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152010 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

African (AFR) AF: 0.0000724 AC: 3 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.49
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.31	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.049
Sift	Benign	0.25	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.35		Loss of catalytic residue at Q41 (P = 0.0696)
MVP		0.25
MPC		0.44
ClinPred		0.097	T
GERP RS		1.7
PromoterAI		-0.0024	Neutral
Varity_R		0.088
gMVP		0.30
Mutation Taster		=95/5	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: rs776085652; hg19: chr14-100111666;