Y-7064150-G-C

Variant names:

• chrY-7064150-G-C
• rs77259694
• NM_033284.2:c.457+1G>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_033284.2(TBL1Y):​c.457+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., 26 hem., cov: 0)
  • Exomes 𝑓: 0.00069 (0 hom. 250 hem.)
• Consequence: TBL1Y NM_033284.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.23

Genes affected

TBL1Y (HGNC:18502): (transducin beta like 1 Y-linked) The protein encoded by this gene has sequence similarity with members of the WD40 repeat-containing protein family. The WD40 group is a large family of proteins, which appear to have a regulatory function. It is believed that the WD40 repeats mediate protein-protein interactions and members of the family are involved in signal transduction, RNA processing, gene regulation, vesicular trafficking, cytoskeletal assembly and may play a role in the control of cytotypic differentiation. This gene is highly similar to TBL1X gene in nucleotide sequence and protein sequence, but the TBL1X gene is located on chromosome X and this gene is on chromosome Y. This gene has three alternatively spliced transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant Y-7064150-G-C is Benign according to our data. Variant chrY-7064150-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 719064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 26 YL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1Y	NM_033284.2	c.457+1G>C		splice_donor_variant, intron_variant	Intron 8 of 18	ENST00000383032.6	NP_150600.1
TBL1Y	NM_134258.2	c.457+1G>C		splice_donor_variant, intron_variant	Intron 7 of 17		NP_599020.1
TBL1Y	NM_134259.2	c.457+1G>C		splice_donor_variant, intron_variant	Intron 7 of 17		NP_599021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1Y	ENST00000383032.6	c.457+1G>C		splice_donor_variant, intron_variant	Intron 8 of 18	1	NM_033284.2	ENSP00000372499.1
TBL1Y	ENST00000346432.3	c.457+1G>C		splice_donor_variant, intron_variant	Intron 7 of 17	1		ENSP00000328879.4
TBL1Y	ENST00000355162.6	c.457+1G>C		splice_donor_variant, intron_variant	Intron 7 of 17	1		ENSP00000347289.2

Frequencies

GnomAD3 genomes AF: 0.000772 AC: 26 AN: 33693 Hom.: 0 Cov.: 0 AF XY: 0.000772 AC XY: 26 AN XY: 33693

Gnomad AFR AF: 0.000116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000267

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0126

Gnomad SAS AF: 0.00137

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00211

GnomAD3 exomes AF: 0.00151 AC: 100 AN: 66112 Hom.: 0 AF XY: 0.00151 AC XY: 100 AN XY: 66112

Gnomad AFR exome AF: 0.000325

Gnomad AMR exome AF: 0.000981

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0171

Gnomad SAS exome AF: 0.0000878

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00382

GnomAD4 exome AF: 0.000689 AC: 250 AN: 362794 Hom.: 0 Cov.: 1 AF XY: 0.000689 AC XY: 250 AN XY: 362794

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0110

Gnomad4 SAS exome AF: 0.000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000137

Gnomad4 OTH exome AF: 0.00666

GnomAD4 genome AF: 0.000770 AC: 26 AN: 33758 Hom.: 0 Cov.: 0 AF XY: 0.000770 AC XY: 26 AN XY: 33758

Gnomad4 AFR AF: 0.000116

Gnomad4 AMR AF: 0.000267

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0126

Gnomad4 SAS AF: 0.00137

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00210

Alfa AF: 0.000841 Hom.: 2

ExAC AF: 0.00176 AC: 122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TBL1Y-related disorder Benign:1

Jan 06, 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). -

Deafness, Y-linked 2 Benign:1

Aug 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.77
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs77259694; hg19: chrY-6932191;