X-70605421-C-T

Position:

• chrX-70605421-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_031276.3(TEX11):​c.2047G>A​(p.Ala683Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,202,574 control chromosomes in the GnomAD database, including 1 homozygotes. There are 81 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., 51 hem., cov: 23)
  • Exomes 𝑓: 0.00015 (0 hom. 30 hem.)
• Consequence: TEX11 NM_031276.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: 0.583

Genes affected

TEX11 (HGNC:11733): (testis expressed 11) This gene is X-linked and is expressed in only male germ cells. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006994188).
• BS2: High Hemizygotes in GnomAd4 at 51 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TEX11	NM_031276.3	c.2047G>A	p.Ala683Thr	missense_variant	24/30	ENST00000374333.7	NP_112566.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TEX11	ENST00000374333.7	c.2047G>A	p.Ala683Thr	missense_variant	24/30	1	NM_031276.3	ENSP00000363453	P2
TEX11	ENST00000344304.3	c.2092G>A	p.Ala698Thr	missense_variant	23/29	5		ENSP00000340995	A2
TEX11	ENST00000395889.6	c.2092G>A	p.Ala698Thr	missense_variant	25/31	2		ENSP00000379226	A2
TEX11	ENST00000374320.6	c.1117G>A	p.Ala373Thr	missense_variant	13/19	2		ENSP00000363440

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 187 AN: 111978 Hom.: 1 Cov.: 23 AF XY: 0.00149 AC XY: 51 AN XY: 34164

Gnomad AFR AF: 0.00592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000283

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000659

GnomAD3 exomes AF: 0.000362 AC: 65 AN: 179744 Hom.: 0 AF XY: 0.000186 AC XY: 12 AN XY: 64392

Gnomad AFR exome AF: 0.00416

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000372

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.000149 AC: 163 AN: 1090544 Hom.: 0 Cov.: 27 AF XY: 0.0000842 AC XY: 30 AN XY: 356502

Gnomad4 AFR exome AF: 0.00504

Gnomad4 AMR exome AF: 0.000286

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000957

Gnomad4 OTH exome AF: 0.000284

GnomAD4 genome AF: 0.00167 AC: 187 AN: 112030 Hom.: 1 Cov.: 23 AF XY: 0.00149 AC XY: 51 AN XY: 34226

Gnomad4 AFR AF: 0.00591

Gnomad4 AMR AF: 0.000283

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000651

Alfa AF: 0.0000935 Hom.: 2

Bravo AF: 0.00187

ESP6500AA AF: 0.00522 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2024	The p.Ala698Thr variant in TEX11 is classified as likely benign because it has been identified in 0.55% (315/57191) of African chromosomes including 72 hemizygotes and 1 homozygote by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). In addition, computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Spermatogenic failure, X-linked, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 28, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	.;.;T;T
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.76	T;T;T;.
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.0070	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	.;.;M;M
MutationTaster	Benign	0.95	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.063
Sift	Uncertain	0.024	D;D;D;D
Sift4G	Uncertain	0.026	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.079
MVP		0.27
MPC		0.65
ClinPred		0.024	T
GERP RS		3.9
Varity_R		0.22
gMVP		0.13

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: rs140984555; hg19: chrX-69825271;