Y-7064105-G-A

Variant names:

• chrY-7064105-G-A
• rs377026718
• NM_033284.2:c.413G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_033284.2(TBL1Y):​c.413G>A​(p.Arg138Gln) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., 11 hem., cov: 0)
  • Exomes 𝑓: 0.00035 (0 hom. 127 hem.)
• Consequence: TBL1Y NM_033284.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 5.32

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014740616).
• BP6: Variant Y-7064105-G-A is Benign according to our data. Variant chrY-7064105-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3033002.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 11 YL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1Y	NM_033284.2	c.413G>A	p.Arg138Gln	missense_variant	Exon 8 of 19	ENST00000383032.6	NP_150600.1
TBL1Y	NM_134258.2	c.413G>A	p.Arg138Gln	missense_variant	Exon 7 of 18		NP_599020.1
TBL1Y	NM_134259.2	c.413G>A	p.Arg138Gln	missense_variant	Exon 7 of 18		NP_599021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1Y	ENST00000383032.6	c.413G>A	p.Arg138Gln	missense_variant	Exon 8 of 19	1	NM_033284.2	ENSP00000372499.1
TBL1Y	ENST00000346432.3	c.413G>A	p.Arg138Gln	missense_variant	Exon 7 of 18	1		ENSP00000328879.4
TBL1Y	ENST00000355162.6	c.413G>A	p.Arg138Gln	missense_variant	Exon 7 of 18	1		ENSP00000347289.2

Frequencies

GnomAD3 genomes AF: 0.000327 AC: 11 AN: 33676 Hom.: 0 Cov.: 0 AF XY: 0.000327 AC XY: 11 AN XY: 33676

Gnomad AFR AF: 0.000233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000270

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00239

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000270 AC: 18 AN: 66764 Hom.: 0 AF XY: 0.000270 AC XY: 18 AN XY: 66764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000665

Gnomad SAS exome AF: 0.000438

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000324

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000350 AC: 127 AN: 362937 Hom.: 0 Cov.: 1 AF XY: 0.000350 AC XY: 127 AN XY: 362937

Gnomad4 AFR exome AF: 0.000141

Gnomad4 AMR exome AF: 0.000105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000633

Gnomad4 SAS exome AF: 0.000535

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000326

Gnomad4 OTH exome AF: 0.000771

GnomAD4 genome AF: 0.000326 AC: 11 AN: 33740 Hom.: 0 Cov.: 0 AF XY: 0.000326 AC XY: 11 AN XY: 33740

Gnomad4 AFR AF: 0.000231

Gnomad4 AMR AF: 0.000269

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00239

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000259 AC: 18

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TBL1Y-related disorder Benign:1

Jan 04, 2023

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
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	18
DANN	Benign	0.71
DEOGEN2	Benign	0.031	T;T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.64	.;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.015	T;T;T
MutationAssessor	Benign	0.69	N;N;N
PROVEAN	Benign	0.45	N;N;N
Sift	Benign	0.63	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.091	B;B;B
Vest4		0.083
MVP		0.10
GERP RS		2.3
Varity_R		0.064
gMVP		0.40

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: rs377026718; hg19: chrY-6932146;