rs150739070

Variant names:

• chr7-22960413-A-C
• rs150739070
• NM_032581.4:c.834T>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_032581.4(HYCC1):​c.834T>G​(p.Val278Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,611,402 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (12 hom.)
• Consequence: HYCC1 NM_032581.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.89
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.05).
• BP6: Variant 7-22960413-A-C is Benign according to our data. Variant chr7-22960413-A-C is described in ClinVar as Benign. ClinVar VariationId is 468356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00123 (187/152282) while in subpopulation EAS AF = 0.0222 (115/5180). AF 95% confidence interval is 0.0189. There are 1 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYCC1	NM_032581.4	MANE Select	c.834T>G	p.Val278Val	splice_region synonymous	Exon 10 of 11	NP_115970.2
	HYCC1	NM_001363466.2		c.834T>G	p.Val278Val	splice_region synonymous	Exon 10 of 12	NP_001350395.1
	HYCC1	NM_001363467.2		c.834T>G	p.Val278Val	splice_region synonymous	Exon 10 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.834T>G	p.Val278Val	splice_region synonymous	Exon 10 of 11	ENSP00000403396.2
	HYCC1	ENST00000440481.6	TSL:1	c.402T>G	p.Val134Val	splice_region synonymous	Exon 9 of 11	ENSP00000397168.2
	HYCC1	ENST00000905181.1		c.834T>G	p.Val278Val	splice_region synonymous	Exon 10 of 11	ENSP00000575240.1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0220

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00230 AC: 576 AN: 250756 AF XY: 0.00235

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0231

Gnomad FIN exome AF: 0.00314

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000986 AC: 1439 AN: 1459120 Hom.: 12 Cov.: 30 AF XY: 0.00105 AC XY: 762 AN XY: 726082

African (AFR) AF: 0.000150 AC: 5 AN: 33414

American (AMR) AF: 0.0000671 AC: 3 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0235 AC: 931 AN: 39598

South Asian (SAS) AF: 0.00111 AC: 96 AN: 86202

European-Finnish (FIN) AF: 0.00308 AC: 163 AN: 52886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000137 AC: 152 AN: 1110130

Other (OTH) AF: 0.00148 AC: 89 AN: 60316

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74470

African (AFR) AF: 0.000241 AC: 10 AN: 41566

American (AMR) AF: 0.000196 AC: 3 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.0222 AC: 115 AN: 5180

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68014

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000244 Hom.: 0

Bravo AF: 0.00122

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hypomyelination and Congenital Cataract (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		2.9
Mutation Taster		=88/12	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: rs150739070; hg19: chr7-23000032;