Genetic Variant TTC7B:p.Thr646Asn (chr14-90610771-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001010854.2(TTC7B):c.1937C>A(p.Thr646Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

TTC7B
NM_001010854.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.64

Variant links:

Genes affected

TTC7B (HGNC:19858): (tetratricopeptide repeat domain 7B) Involved in phosphatidylinositol phosphate biosynthetic process and protein localization to plasma membrane. Located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TTC7B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC7B	NM_001010854.2 link	c.1937C>A	p.Thr646Asn	missense_variant	Exon 17 of 20	ENST00000328459.11	NP_001010854.1	Q86TV6-1Q6PIF1
TTC7B	NM_001401365.1 link	c.1937C>A	p.Thr646Asn	missense_variant	Exon 17 of 22		NP_001388294.1
TTC7B	NM_001320421.2 link	c.1631C>A	p.Thr544Asn	missense_variant	Exon 17 of 21		NP_001307350.1	Q86TV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC7B	ENST00000328459.11 link	c.1937C>A	p.Thr646Asn	missense_variant	Exon 17 of 20	1	NM_001010854.2	ENSP00000336127.4		Q86TV6-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1937C>A (p.T646N) alteration is located in exon 17 (coding exon 17) of the TTC7B gene. This alteration results from a C to A substitution at nucleotide position 1937, causing the threonine (T) at amino acid position 646 to be replaced by an asparagine (N). 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

0.17

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

T;T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.010

MetaRNN

Uncertain

0.44

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.2

M;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.21

T;T;D

Sift4G

Benign

0.37

T;T;D

Polyphen

1.0

D;.;.

Vest4

0.81

MVP

0.21

MPC

0.41

ClinPred

0.95

GERP RS

5.9

Varity_R

0.32

gMVP

0.48

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