NM_019022.5:c.795-71A>T

Variant names:

• chr18-68684314-T-A
• rs17079562
• NM_019022.5:c.795-71A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019022.5(TMX3):​c.795-71A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,492,968 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (138 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (105 hom.)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0600
• Publications: 1 publications found

Genes affected

TMX3 (HGNC:24718): (thioredoxin related transmembrane protein 3) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The canonical protein encoded by this gene has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, one transmembrane domain and a C-terminal ER-retention sequence. This gene is expressed in many tissues but has its highest expression in heart and skeletal muscle. It is expressed in the retinal neuroepithelium and lens epithelium in the developing murine eye and haploinsufficiency of this gene in humans and zebrafish is associated with microphthalmia. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2017]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-68684314-T-A is Benign according to our data. Variant chr18-68684314-T-A is described in ClinVar as Benign. ClinVar VariationId is 1241037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019022.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMX3	NM_019022.5	MANE Select	c.795-71A>T		intron	N/A	NP_061895.3
	TMX3	NM_001350514.2		c.714-71A>T		intron	N/A	NP_001337443.1
	TMX3	NM_001350515.2		c.372-71A>T		intron	N/A	NP_001337444.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMX3	ENST00000299608.7	TSL:1 MANE Select	c.795-71A>T		intron	N/A	ENSP00000299608.2	Q96JJ7-1
	TMX3	ENST00000564631.5	TSL:1	n.*479-71A>T		intron	N/A	ENSP00000456587.1	H3BVI1
	TMX3	ENST00000915516.1		c.918-71A>T		intron	N/A	ENSP00000585575.1

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3494 AN: 152158 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00321 AC: 4305 AN: 1340692 Hom.: 105 Cov.: 20 AF XY: 0.00288 AC XY: 1942 AN XY: 673274

African (AFR) AF: 0.0755 AC: 2303 AN: 30492

American (AMR) AF: 0.00669 AC: 287 AN: 42918

Ashkenazi Jewish (ASJ) AF: 0.000726 AC: 18 AN: 24796

East Asian (EAS) AF: 0.00 AC: 0 AN: 38978

South Asian (SAS) AF: 0.000342 AC: 28 AN: 81906

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52606

Middle Eastern (MID) AF: 0.0159 AC: 87 AN: 5476

European-Non Finnish (NFE) AF: 0.00118 AC: 1185 AN: 1007244

Other (OTH) AF: 0.00704 AC: 396 AN: 56276

GnomAD4 genome AF: 0.0230 AC: 3507 AN: 152276 Hom.: 138 Cov.: 32 AF XY: 0.0218 AC XY: 1620 AN XY: 74454

African (AFR) AF: 0.0767 AC: 3189 AN: 41556

American (AMR) AF: 0.0106 AC: 163 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00157 AC: 107 AN: 67992

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.0192 Hom.: 10

Bravo AF: 0.0262

Asia WGS AF: 0.00608 AC: 21 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.2
DANN	Benign	0.69
PhyloP100		0.060
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17079562; hg19: chr18-66351551;