10-80514035-C-T

Variant names:

• chr10-80514035-C-T
• NM_030927.4:c.593C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_030927.4(TSPAN14):​c.593C>T​(p.Thr198Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSPAN14 NM_030927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.81
• Publications: 0 publications found

Genes affected

TSPAN14 (HGNC:23303): (tetraspanin 14) Enables enzyme binding activity. Involved in positive regulation of Notch signaling pathway; protein localization to plasma membrane; and protein maturation. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030927.4. 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
	TSPAN14	NM_030927.4	MANE Select	c.593C>T	p.Thr198Ile	missense	Exon 7 of 9	NP_112189.2	Q8NG11-1
	TSPAN14	NM_001351266.2		c.593C>T	p.Thr198Ile	missense	Exon 8 of 10	NP_001338195.1	Q8NG11-1
	TSPAN14	NM_001351267.4		c.593C>T	p.Thr198Ile	missense	Exon 9 of 11	NP_001338196.1	Q8NG11-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPAN14	ENST00000429989.8	TSL:1 MANE Select	c.593C>T	p.Thr198Ile	missense	Exon 7 of 9	ENSP00000396270.2	Q8NG11-1
	TSPAN14	ENST00000372164.7	TSL:1	c.542C>T	p.Thr181Ile	missense	Exon 6 of 8	ENSP00000361237.3	Q8NG11-2
	TSPAN14	ENST00000714439.1		c.635C>T	p.Thr212Ile	missense	Exon 9 of 11	ENSP00000519708.1	A0AAQ5BI32

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461626 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727082

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111906

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.30
Sift	Benign	0.26	T
Sift4G	Benign	0.13	T
Polyphen		0.92	P
Vest4		0.62
MutPred		0.63		Gain of sheet (P = 0.0477)
MVP		0.25
MPC		1.9
ClinPred		0.95	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.85
Mutation Taster		=36/64	disease causing

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

Other links and lift over

hg19: chr10-82273791;