chr7-22945663-T-C

Variant names:

• chr7-22945663-T-C
• rs143894913
• NM_032581.4:c.1492A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.42
• Publications: 2 publications found

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

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032581.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYCC1	NM_032581.4	MANE Select	c.1492A>G	p.Thr498Ala	missense	Exon 11 of 11	NP_115970.2
	HYCC1	NM_001363466.2		c.*528A>G		3_prime_UTR	Exon 12 of 12	NP_001350395.1
	HYCC1	NM_001363467.2		c.*486A>G		3_prime_UTR	Exon 12 of 12	NP_001350396.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYCC1	ENST00000432176.7	TSL:1 MANE Select	c.1492A>G	p.Thr498Ala	missense	Exon 11 of 11	ENSP00000403396.2
	HYCC1	ENST00000440481.6	TSL:1	c.*528A>G		3_prime_UTR	Exon 11 of 11	ENSP00000397168.2
	HYCC1	ENST00000681766.1		c.1438A>G	p.Thr480Ala	missense	Exon 11 of 11	ENSP00000505161.1

Frequencies

GnomAD3 genomes AF: 0.00399 AC: 607 AN: 152114 Hom.: 3 Cov.: 32

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

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.: 4 Cov.: 31 AF XY: 0.000415 AC XY: 302 AN XY: 727112

African (AFR) AF: 0.0119 AC: 399 AN: 33454

American (AMR) AF: 0.00186 AC: 83 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5762

European-Non Finnish (NFE) AF: 0.000123 AC: 137 AN: 1111812

Other (OTH) AF: 0.000961 AC: 58 AN: 60374

GnomAD4 genome AF: 0.00402 AC: 612 AN: 152232 Hom.: 3 Cov.: 32 AF XY: 0.00388 AC XY: 289 AN XY: 74430

African (AFR) AF: 0.0134 AC: 557 AN: 41554

American (AMR) AF: 0.00210 AC: 32 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68000

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00156 Hom.: 3

Bravo AF: 0.00480

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0157 AC: 69

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00151 AC: 183

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign: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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.018
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.21
Sift	Benign	0.086	T
Sift4G	Benign	0.15	T
Polyphen		0.034	B
Vest4		0.093
MVP		0.37
MPC		0.13
ClinPred		0.023	T
GERP RS		6.2
Varity_R		0.10
gMVP		0.17
Mutation Taster		=81/19	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: rs143894913; hg19: chr7-22985282;