NM_001127258.3:c.94C>T

Variant names:

• chr14-99645301-C-T
• rs1039035840
• NM_001127258.3:c.94C>T

Variant summary

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

The NM_001127258.3(HHIPL1):​c.94C>T​(p.Pro32Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,450,334 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: HHIPL1 NM_001127258.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.80
• 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.94C>T	p.Pro32Ser	missense	Exon 1 of 9	NP_001120730.1	F1T0G3
	HHIPL1	NM_032425.5		c.94C>T	p.Pro32Ser	missense	Exon 1 of 8	NP_115801.3	Q96JK4-2
	HHIPL1	NM_001329411.2		c.61-6923C>T		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.94C>T	p.Pro32Ser	missense	Exon 1 of 9	ENSP00000330601.5	Q96JK4-1
	HHIPL1	ENST00000357223.2	TSL:1	c.94C>T	p.Pro32Ser	missense	Exon 1 of 8	ENSP00000349757.2	Q96JK4-2
	HHIPL1	ENST00000949017.1		c.94C>T	p.Pro32Ser	missense	Exon 1 of 9	ENSP00000619076.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1298246 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 639522

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

African (AFR) AF: 0.00 AC: 0 AN: 26248

American (AMR) AF: 0.0000862 AC: 2 AN: 23212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22496

East Asian (EAS) AF: 0.00 AC: 0 AN: 27680

South Asian (SAS) AF: 0.00 AC: 0 AN: 69292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3776

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1038214

Other (OTH) AF: 0.00 AC: 0 AN: 53314

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15268

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.29
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.086	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.45		Loss of helix (P = 0.0237)
MVP		0.81
MPC		1.3
ClinPred		1.0	D
GERP RS		3.2
PromoterAI		0.019	Neutral
Varity_R		0.48
gMVP		0.64
Mutation Taster		=63/37	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: rs1039035840; hg19: chr14-100111638;