18-56614600-T-C

Position:

• chr18-56614600-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004786.3(TXNL1):​c.563-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00502 in 1,604,856 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (169 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (136 hom.)
• Consequence: TXNL1 NM_004786.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001076
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0610

Genes affected

TXNL1 (HGNC:12436): (thioredoxin like 1) Enables disulfide oxidoreductase activity. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TXNL1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 18-56614600-T-C is Benign according to our data. Variant chr18-56614600-T-C is described in ClinVar as [Benign]. Clinvar id is 768936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNL1	NM_004786.3	c.563-4A>G		splice_region_variant, intron_variant		ENST00000217515.11	NP_004777.1
TXNL1	XM_024451289.2	c.563-4A>G		splice_region_variant, intron_variant			XP_024307057.1
TXNL1	XM_024451290.2	c.563-4A>G		splice_region_variant, intron_variant			XP_024307058.1
TXNL1	NR_024546.2	n.820-4A>G		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNL1	ENST00000217515.11	c.563-4A>G		splice_region_variant, intron_variant		1	NM_004786.3	ENSP00000217515.5
TXNL1	ENST00000586262.5	c.548-4A>G		splice_region_variant, intron_variant		1		ENSP00000468165.1
TXNL1	ENST00000590954.5	c.563-4A>G		splice_region_variant, intron_variant		2		ENSP00000464918.1
TXNL1	ENST00000587807.5	n.*458-4A>G		splice_region_variant, intron_variant		2		ENSP00000467317.1

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 4003 AN: 152134 Hom.: 169 Cov.: 32

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00704 AC: 1706 AN: 242298 Hom.: 64 AF XY: 0.00520 AC XY: 682 AN XY: 131264

Gnomad AFR exome AF: 0.0904

Gnomad AMR exome AF: 0.00591

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.00477

GnomAD4 exome AF: 0.00278 AC: 4043 AN: 1452604 Hom.: 136 Cov.: 30 AF XY: 0.00234 AC XY: 1692 AN XY: 722592

Gnomad4 AFR exome AF: 0.0904

Gnomad4 AMR exome AF: 0.00734

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000177

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000301

Gnomad4 OTH exome AF: 0.00617

GnomAD4 genome AF: 0.0263 AC: 4009 AN: 152252 Hom.: 169 Cov.: 32 AF XY: 0.0250 AC XY: 1865 AN XY: 74454

Gnomad4 AFR AF: 0.0907

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.0114 Hom.: 20

Bravo AF: 0.0301

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.9
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		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: rs17090267; hg19: chr18-54281831;