14-90541559-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001010854.2(TTC7B):c.2341A>C(p.Ser781Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000234 in 1,453,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: TTC7B NM_001010854.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2700684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC7B	NM_001010854.2	c.2341A>C	p.Ser781Arg	missense_variant	20/20	ENST00000328459.11
TTC7B	NM_001401365.1	c.2554A>C	p.Ser852Arg	missense_variant	22/22
TTC7B	NM_001320421.2	c.2086A>C	p.Ser696Arg	missense_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC7B	ENST00000328459.11	c.2341A>C	p.Ser781Arg	missense_variant	20/20	1	NM_001010854.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000810 AC: 2 AN: 246786 Hom.: 0 AF XY: 0.00000749 AC XY: 1 AN XY: 133472

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000234 AC: 34 AN: 1453428 Hom.: 0 Cov.: 32 AF XY: 0.0000222 AC XY: 16 AN XY: 721550

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: 0.0000307

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.2341A>C (p.S781R) alteration is located in exon 20 (coding exon 20) of the TTC7B gene. This alteration results from a A to C substitution at nucleotide position 2341, causing the serine (S) at amino acid position 781 to be replaced by an arginine (R). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.054	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
MVP		0.23
ClinPred		0.68	D
GERP RS		5.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs1307560995; hg19: chr14-91007903;