Genetic Variant HHIPL1:p.Thr102Met (chr14-99652273-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001127258.3(HHIPL1):c.305C>T(p.Thr102Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

HHIPL1
NM_001127258.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Publications

2 publications found

Variant links:

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]

HHIPL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.762

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HHIPL1	NM_001127258.3	MANE Select	c.305C>T	p.Thr102Met	missense	Exon 2 of 9	NP_001120730.1	F1T0G3
HHIPL1	NM_032425.5		c.305C>T	p.Thr102Met	missense	Exon 2 of 8	NP_115801.3	Q96JK4-2
HHIPL1	NM_001329411.2		c.110C>T	p.Thr37Met	missense	Exon 3 of 9	NP_001316340.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HHIPL1	ENST00000330710.10	TSL:1 MANE Select	c.305C>T	p.Thr102Met	missense	Exon 2 of 9	ENSP00000330601.5	Q96JK4-1
HHIPL1	ENST00000357223.2	TSL:1	c.305C>T	p.Thr102Met	missense	Exon 2 of 8	ENSP00000349757.2	Q96JK4-2
HHIPL1	ENST00000949017.1		c.305C>T	p.Thr102Met	missense	Exon 2 of 9	ENSP00000619076.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250628

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461150

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726878

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111830

Other (OTH)

AF:

0.0000166

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.034

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.6

PhyloP100

7.9

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.30

Sift

Benign

0.033

Sift4G

Benign

0.096

Polyphen

1.0

Vest4

0.79

MVP

0.64

MPC

1.3

ClinPred

0.96

GERP RS

4.8

Varity_R

0.24

gMVP

0.71

Mutation Taster

=48/52

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over