19-15011168-C-T

Variant names:

• chr19-15011168-C-T
• rs765658984
• NM_173482.3:c.343C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173482.3(TEKTL1):​c.343C>T​(p.Arg115Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R115G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TEKTL1 NM_173482.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.53
• Publications: 0 publications found

Genes affected

TEKTL1 (HGNC:26866): (tektin like 1) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

SLC1A6 (HGNC:10944): (solute carrier family 1 member 6) Predicted to enable high-affinity glutamate transmembrane transporter activity. Involved in neurotransmitter uptake. Located in intermediate filament cytoskeleton and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000302149 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173482.3. 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
	TEKTL1	NM_173482.3	MANE Select	c.343C>T	p.Arg115Cys	missense	Exon 1 of 7	NP_775753.2	Q8IYK2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEKTL1	ENST00000292574.4	TSL:1 MANE Select	c.343C>T	p.Arg115Cys	missense	Exon 1 of 7	ENSP00000292574.2	Q8IYK2
	SLC1A6	ENST00000595863.1	TSL:3	c.-8+11736G>A		intron	N/A	ENSP00000469551.1	M0QY32
	ENSG00000302149	ENST00000784685.1		n.341-16936G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1348682 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 662848

African (AFR) AF: 0.00 AC: 0 AN: 29026

American (AMR) AF: 0.00 AC: 0 AN: 26568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21902

East Asian (EAS) AF: 0.00 AC: 0 AN: 35370

South Asian (SAS) AF: 0.00 AC: 0 AN: 71254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4580

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062094

Other (OTH) AF: 0.00 AC: 0 AN: 55674

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74288

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.49		Loss of MoRF binding (P = 0.0041)
MVP		0.65
MPC		1.4
ClinPred		1.0	D
GERP RS		2.7
PromoterAI		-0.015	Neutral
Varity_R		0.71
gMVP		0.57
Mutation Taster		=29/71	disease causing

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: rs765658984; hg19: chr19-15121980;