rs143894913

Positions:

• chr7-22945663-T-C

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 430052.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYCC1	NM_032581.4	c.1492A>G	p.Thr498Ala	missense_variant	11/11	ENST00000432176.7	NP_115970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HYCC1	ENST00000432176.7	c.1492A>G	p.Thr498Ala	missense_variant	11/11	1	NM_032581.4	ENSP00000403396

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

GnomAD3 exomes AF: 0.00124 AC: 312 AN: 250766 Hom.: 1 AF XY: 0.000834 AC XY: 113 AN XY: 135484

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 SAS 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

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.000961

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

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.00210

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000746 Hom.: 0

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

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	HYCC1: BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2017	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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D
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

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

LitVar

Other links and lift over

dbSNP: rs143894913; hg19: chr7-22985282;