10-100235720-T-G

Variant names:

• chr10-100235720-T-G
• rs139693285
• NM_018294.6:c.1419A>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018294.6(CWF19L1):​c.1419A>C​(p.Thr473Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,612,474 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: CWF19L1 NM_018294.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.899

Genes affected

CWF19L1 (HGNC:25613): (CWF19 like cell cycle control factor 1) This gene encodes a member of the CWF19 protein family. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia-17 and mild cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 10-100235720-T-G is Benign according to our data. Variant chr10-100235720-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 715239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.899 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000906 (138/152348) while in subpopulation NFE AF= 0.00168 (114/68042). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CWF19L1	NM_018294.6	c.1419A>C	p.Thr473Thr	synonymous_variant	Exon 13 of 14	ENST00000354105.10	NP_060764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CWF19L1	ENST00000354105.10	c.1419A>C	p.Thr473Thr	synonymous_variant	Exon 13 of 14	1	NM_018294.6	ENSP00000326411.6

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000852 AC: 213 AN: 250080 Hom.: 0 AF XY: 0.000872 AC XY: 118 AN XY: 135340

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000681

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00140 AC: 2042 AN: 1460126 Hom.: 2 Cov.: 29 AF XY: 0.00138 AC XY: 1003 AN XY: 726466

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000907

Gnomad4 NFE exome AF: 0.00172

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000913 AC XY: 68 AN XY: 74500

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000842

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00115

EpiControl AF: 0.00142

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CWF19L1: BP4, BP7 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CWF19L1-related disorder Benign:1

Feb 19, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.3
DANN	Benign	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

Publications

LitVar

Other links and lift over

dbSNP: rs139693285; hg19: chr10-101995477;