chrX-70605421-C-T

Variant names:

• chrX-70605421-C-T
• rs140984555
• NM_031276.3:c.2047G>A

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 rank	MANE	Protein	UniProt
TEX11	NM_031276.3	c.2047G>A	p.Ala683Thr	missense_variant	Exon 24 of 30	ENST00000374333.7	NP_112566.2

Ensembl

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

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

Feb 21, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spermatogenic failure, X-linked, 2 Pathogenic:1

May 28, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Benign:1

Dec 11, 2024

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
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
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;