rs3735231

Variant names:

• chr7-22976212-T-C
• rs3735231
• NM_032581.4:c.624A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-22976212-T-C
• chr7-22976212-T-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_032581.4(HYCC1):​c.624A>G​(p.Ser208Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,595,058 control chromosomes in the GnomAD database, including 99,736 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9511 hom., cov: 32)
  • Exomes 𝑓: 0.35 (90225 hom.)
• Consequence: HYCC1 NM_032581.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.007816
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.04
• Publications: 23 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=0.103).
• BP6: Variant 7-22976212-T-C is Benign according to our data. Variant chr7-22976212-T-C is described in ClinVar as Benign. ClinVar VariationId is 21726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYCC1	NM_032581.4	c.624A>G	p.Ser208Ser	splice_region_variant, synonymous_variant	Exon 7 of 11	ENST00000432176.7	NP_115970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HYCC1	ENST00000432176.7	c.624A>G	p.Ser208Ser	splice_region_variant, synonymous_variant	Exon 7 of 11	1	NM_032581.4	ENSP00000403396.2

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53611 AN: 151996 Hom.: 9502 Cov.: 32

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.370 AC: 92045 AN: 248962 AF XY: 0.368

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.418

Gnomad EAS exome AF: 0.485

Gnomad FIN exome AF: 0.348

Gnomad NFE exome AF: 0.348

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.351 AC: 506122 AN: 1442944 Hom.: 90225 Cov.: 29 AF XY: 0.351 AC XY: 252215 AN XY: 718942

African (AFR) AF: 0.351 AC: 11605 AN: 33052

American (AMR) AF: 0.380 AC: 16963 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 10980 AN: 26018

East Asian (EAS) AF: 0.478 AC: 18906 AN: 39554

South Asian (SAS) AF: 0.374 AC: 32105 AN: 85814

European-Finnish (FIN) AF: 0.361 AC: 19042 AN: 52718

Middle Eastern (MID) AF: 0.341 AC: 1955 AN: 5726

European-Non Finnish (NFE) AF: 0.341 AC: 373243 AN: 1095628

Other (OTH) AF: 0.357 AC: 21323 AN: 59764

GnomAD4 genome AF: 0.353 AC: 53654 AN: 152114 Hom.: 9511 Cov.: 32 AF XY: 0.353 AC XY: 26219 AN XY: 74376

African (AFR) AF: 0.354 AC: 14676 AN: 41486

American (AMR) AF: 0.339 AC: 5173 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 1489 AN: 3472

East Asian (EAS) AF: 0.472 AC: 2444 AN: 5182

South Asian (SAS) AF: 0.358 AC: 1726 AN: 4826

European-Finnish (FIN) AF: 0.349 AC: 3694 AN: 10570

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.343 AC: 23324 AN: 67984

Other (OTH) AF: 0.323 AC: 680 AN: 2108

Alfa AF: 0.352 Hom.: 6949

Bravo AF: 0.356

Asia WGS AF: 0.387 AC: 1347 AN: 3478

EpiCase AF: 0.340

EpiControl AF: 0.342

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelination and Congenital Cataract Benign:3

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Apr 02, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0078
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.010		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: rs3735231; hg19: chr7-23015831; COSMIC: COSV69016766; COSMIC: COSV69016766;