14-90610828-C-A

Variant names:

• chr14-90610828-C-A
• rs373513556
• NM_001010854.2:c.1880G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001010854.2(TTC7B):​c.1880G>T​(p.Arg627Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,206 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R627H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TTC7B NM_001010854.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.63
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010854.2. 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
	TTC7B	NM_001010854.2	MANE Select	c.1880G>T	p.Arg627Leu	missense	Exon 17 of 20	NP_001010854.1	Q86TV6-1
	TTC7B	NM_001401365.1		c.1880G>T	p.Arg627Leu	missense	Exon 17 of 22	NP_001388294.1
	TTC7B	NM_001320421.2		c.1574G>T	p.Arg525Leu	missense	Exon 17 of 21	NP_001307350.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC7B	ENST00000328459.11	TSL:1 MANE Select	c.1880G>T	p.Arg627Leu	missense	Exon 17 of 20	ENSP00000336127.4	Q86TV6-1
	TTC7B	ENST00000553972.5	TSL:1	c.290G>T	p.Arg97Leu	missense	Exon 3 of 7	ENSP00000451440.1	A0A0C4DGK5
	TTC7B	ENST00000963264.1		c.1880G>T	p.Arg627Leu	missense	Exon 17 of 21	ENSP00000633323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461206 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726954

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111410

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.46		Gain of catalytic residue at P622 (P = 0.0075)
MVP		0.41
MPC		0.75
ClinPred		0.96	D
GERP RS		5.9
PromoterAI		-0.025	Neutral
Varity_R		0.30
gMVP		0.56
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs373513556; hg19: chr14-91077172;