5-134874531-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PM2 PP3_Strong PP5_Moderate

The NM_024715.4(TXNDC15):c.103+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TXNDC15 NM_024715.4 splice_donor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 2.69

Genes affected

TXNDC15 (HGNC:20652): (thioredoxin domain containing 15) This gene encodes a member of the thioredoxin superfamily. Members of this family are characterized by a conserved active motif called the thioredoxin fold that catalyzes disulfide bond formation and isomerization. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-134874531-G-A is Pathogenic according to our data. Variant chr5-134874531-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 266075.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNDC15	NM_024715.4	c.103+1G>A		splice_donor_variant		ENST00000358387.9
TXNDC15	NM_001350735.2	c.-102+48G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNDC15	ENST00000358387.9	c.103+1G>A		splice_donor_variant		1	NM_024715.4	P1
TXNDC15	ENST00000507024.5	c.56+48G>A		intron_variant, NMD_transcript_variant		1
TXNDC15	ENST00000511070.5	c.103+1G>A		splice_donor_variant, NMD_transcript_variant		1
TXNDC15	ENST00000506916.1	c.103+1G>A		splice_donor_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445928 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719786

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Meckel syndrome 14 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 13, 2022	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -

Meckel-Gruber syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre

-

Loss of function, autozygosity mapping, gene independently mutated in three families with Meckel-Gruber syndrome, experimental evidence linking TXNDC15 to ciliogenesis -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	34
Dann	Uncertain	0.98
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Benign	0.28	N
MutationTaster	Benign	1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.81		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: rs886039792; hg19: chr5-134210221;