Genetic Variant TEKTIP1:p.Arg56Trp (chr19-3543317-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001135580.2(TEKTIP1):c.166C>T(p.Arg56Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000671 in 1,549,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

TEKTIP1
NM_001135580.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0190

Variant links:

Genes affected

TEKTIP1 (HGNC:34496): (tektin bundle interacting protein 1)

TEKTIP1 links:

MFSD12 (HGNC:28299): (major facilitator superfamily domain containing 12) Enables cysteine transmembrane transporter activity. Involved in cysteine transmembrane transport; pigment metabolic process involved in pigmentation; and regulation of melanin biosynthetic process. Located in lysosome and melanosome. Part of late endosome. [provided by Alliance of Genome Resources, Apr 2022]

MFSD12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06261644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEKTIP1	NM_001135580.2 link	c.166C>T	p.Arg56Trp	missense_variant	Exon 2 of 4	ENST00000329493.6	NP_001129052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEKTIP1	ENST00000329493.6 link	c.166C>T	p.Arg56Trp	missense_variant	Exon 2 of 4	2	NM_001135580.2	ENSP00000327950.4		A6NCJ1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000165

AC:

AN:

151914

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

81068

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000731

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000512

Gnomad OTH exome

AF:

0.000233

GnomAD4 exome

AF:

0.0000651

AC:

AN:

1397036

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

689090

show subpopulations

Gnomad4 AFR exome

AF:

0.000158

Gnomad4 AMR exome

AF:

0.000504

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.000101

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000528

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000830

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000368

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.166C>T (p.R56W) alteration is located in exon 2 (coding exon 2) of the C19orf71 gene. This alteration results from a C to T substitution at nucleotide position 166, causing the arginine (R) at amino acid position 56 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.58

M_CAP

Benign

0.026

MetaRNN

Benign

0.063

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.9

PROVEAN

Pathogenic

-5.1

REVEL

Benign

0.064

Sift

Benign

0.060

Sift4G

Uncertain

0.0020

Polyphen

0.0060

Vest4

0.21

MVP

0.22

ClinPred

0.060

GERP RS

-1.4

Varity_R

0.10

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over