14-90617943-G-T

Variant names:

• chr14-90617943-G-T
• NM_001010854.2:c.1854C>A

Variant summary

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

The NM_001010854.2(TTC7B):​c.1854C>A​(p.Asn618Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TTC7B NM_001010854.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

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=0.33790863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC7B	NM_001010854.2	c.1854C>A	p.Asn618Lys	missense_variant	Exon 16 of 20	ENST00000328459.11	NP_001010854.1
TTC7B	NM_001401365.1	c.1854C>A	p.Asn618Lys	missense_variant	Exon 16 of 22		NP_001388294.1
TTC7B	NM_001320421.2	c.1548C>A	p.Asn516Lys	missense_variant	Exon 16 of 21		NP_001307350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC7B	ENST00000328459.11	c.1854C>A	p.Asn618Lys	missense_variant	Exon 16 of 20	1	NM_001010854.2	ENSP00000336127.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1854C>A (p.N618K) alteration is located in exon 16 (coding exon 16) of the TTC7B gene. This alteration results from a C to A substitution at nucleotide position 1854, causing the asparagine (N) at amino acid position 618 to be replaced by a lysine (K). 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	Pathogenic	0.60
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T;T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.028	D;T;D
Sift4G	Uncertain	0.049	D;T;D
Polyphen		0.98	D;.;.
Vest4		0.73
MutPred		0.50		Gain of catalytic residue at P622 (P = 0.0075);.;.;
MVP		0.093
MPC		0.55
ClinPred		0.86	D
GERP RS		3.6
Varity_R		0.38
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-91084287;