chr7-22942099-CTCTG-C

Variant names:

• chr7-22942099-CTCTG-C
• rs545140159
• NM_032581.4:c.*3486_*3489delCAGA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_032581.4(HYCC1):​c.*3486_*3489delCAGA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 152,166 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.00038 (0 hom., cov: 32)
• Consequence: HYCC1 NM_032581.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.804
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000381 (58/152166) while in subpopulation AMR AF = 0.00314 (48/15276). AF 95% confidence interval is 0.00243. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYCC1	NM_032581.4	MANE Select	c.*3486_*3489delCAGA		3_prime_UTR	Exon 11 of 11	NP_115970.2
	HYCC1	NM_001363466.2		c.*4088_*4091delCAGA		3_prime_UTR	Exon 12 of 12	NP_001350395.1	Q9BYI3-3
	HYCC1	NM_001363467.2		c.*4046_*4049delCAGA		3_prime_UTR	Exon 12 of 12	NP_001350396.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYCC1	ENST00000432176.7	TSL:1 MANE Select	c.*3486_*3489delCAGA		3_prime_UTR	Exon 11 of 11	ENSP00000403396.2	Q9BYI3-1
	HYCC1	ENST00000440481.6	TSL:1	c.*4088_*4091delCAGA		3_prime_UTR	Exon 11 of 11	ENSP00000397168.2	H7C0W7
	HYCC1	ENST00000679826.1		c.*3486_*3489delCAGA		3_prime_UTR	Exon 12 of 12	ENSP00000505460.1	A0A7P0T943

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

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: 0.00

Gnomad OTH AF: 0.00383

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74378

African (AFR) AF: 0.0000482 AC: 2 AN: 41522

American (AMR) AF: 0.00314 AC: 48 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000888

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hypomyelination and Congenital Cataract (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.80

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: rs545140159; hg19: chr7-22981718;