14-99645329-A-C

Variant names:

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

Variant summary

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

The NM_001127258.3(HHIPL1):​c.122A>C​(p.Gln41Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000765 in 1,307,208 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 34)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>C	p.Gln41Pro	missense	Exon 1 of 9	NP_001120730.1	F1T0G3
	HHIPL1	NM_032425.5		c.122A>C	p.Gln41Pro	missense	Exon 1 of 8	NP_115801.3	Q96JK4-2
	HHIPL1	NM_001329411.2		c.61-6895A>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.122A>C	p.Gln41Pro	missense	Exon 1 of 9	ENSP00000330601.5	Q96JK4-1
	HHIPL1	ENST00000357223.2	TSL:1	c.122A>C	p.Gln41Pro	missense	Exon 1 of 8	ENSP00000349757.2	Q96JK4-2
	HHIPL1	ENST00000949017.1		c.122A>C	p.Gln41Pro	missense	Exon 1 of 9	ENSP00000619076.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000136 AC: 1 AN: 73372 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.65e-7 AC: 1 AN: 1307208 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: 0.0000408 AC: 1 AN: 24494

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 Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.15
Sift	Benign	0.096	T
Sift4G	Benign	0.24	T
Polyphen		0.48	P
Vest4		0.55
MutPred		0.37		Loss of stability (P = 0.0461)
MVP		0.33
MPC		0.96
ClinPred		0.73	D
GERP RS		1.7
PromoterAI		0.11	Neutral
Varity_R		0.43
gMVP		0.62
Mutation Taster		=85/15	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;