rs143894913

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032581.4(HYCC1):c.1492A>G(p.Thr498Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000805 in 1,613,822 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0040 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 4 hom. )

Consequence

HYCC1
NM_032581.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.42

Publications

2 publications found

Variant links:

Genes affected

HYCC1 (HGNC:24587): (hyccin PI4KA lipid kinase complex subunit 1) The protein encoded by this gene may play a part in the beta-catenin/Lef signaling pathway. Expression of this gene is down-regulated by beta-catenin. Defects in this gene are a cause of hypomyelination with congenital cataract (HCC). [provided by RefSeq, Oct 2008]

HYCC1 Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 5
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

HYCC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030252337).

BP6

Variant 7-22945663-T-C is Benign according to our data. Variant chr7-22945663-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 430052.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00402 (612/152232) while in subpopulation AFR AF = 0.0134 (557/41554). AF 95% confidence interval is 0.0125. There are 3 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYCC1	NM_032581.4 link	c.1492A>G	p.Thr498Ala	missense_variant	Exon 11 of 11	ENST00000432176.7	NP_115970.2	Q9BYI3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HYCC1	ENST00000432176.7 link	c.1492A>G	p.Thr498Ala	missense_variant	Exon 11 of 11	1	NM_032581.4	ENSP00000403396.2		Q9BYI3-1

Frequencies

GnomAD3 genomes

AF:

0.00399

AC:

607

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00124

AC:

312

AN:

250766

AF XY:

0.000834

show subpopulations

Gnomad AFR exome

AF:

0.0144

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000818

GnomAD4 exome

AF:

0.000470

AC:

687

AN:

1461590

Hom.:

Cov.:

AF XY:

0.000415

AC XY:

302

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.0119

AC:

399

AN:

33454

American (AMR)

AF:

0.00186

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000123

AC:

137

AN:

1111812

Other (OTH)

AF:

0.000961

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00402

AC:

612

AN:

152232

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0134

AC:

557

AN:

41554

American (AMR)

AF:

0.00210

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68000

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

121

151

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:

0.00156

Hom.:

Bravo

AF:

0.00480

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0157

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00151

AC:

183

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HYCC1: BP4, BS1, BS2 -

May 18, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The T498A variant in the FAM126A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T498A variant is observed in 154/10400 (1.48%) alleles from individuals of African background in large population cohorts with no homozygous control individuals reported (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T498A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret T498A as a variant of uncertain significance. -

Hypomyelination and Congenital Cataract

Benign:1

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.075

Eigen

Benign

-0.018

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.55

PhyloP100

1.4

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

REVEL

Benign

0.21

Sift

Benign

0.086

Sift4G

Benign

0.15

Polyphen

0.034

Vest4

0.093

MVP

0.37

MPC

0.13

ClinPred

0.023

GERP RS

6.2

Varity_R

0.10

gMVP

0.17

Mutation Taster

=81/19

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over