chr14-90644198-G-C

Variant names:

• chr14-90644198-G-C
• NM_001010854.2:c.1601C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001010854.2(TTC7B):​c.1601C>G​(p.Ala534Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000486 in 1,441,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: TTC7B NM_001010854.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• 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]

TTC7B-AS1 (HGNC:56196): (TTC7B antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

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.1601C>G	p.Ala534Gly	missense	Exon 15 of 20	NP_001010854.1	Q86TV6-1
	TTC7B	NM_001401365.1		c.1601C>G	p.Ala534Gly	missense	Exon 15 of 22	NP_001388294.1
	TTC7B	NM_001320421.2		c.1295C>G	p.Ala432Gly	missense	Exon 15 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.1601C>G	p.Ala534Gly	missense	Exon 15 of 20	ENSP00000336127.4	Q86TV6-1
	TTC7B	ENST00000553972.5	TSL:1	c.11C>G	p.Ala4Gly	missense	Exon 1 of 7	ENSP00000451440.1	A0A0C4DGK5
	TTC7B-AS1	ENST00000557007.1	TSL:1	n.92-546G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000486 AC: 7 AN: 1441288 Hom.: 0 Cov.: 32 AF XY: 0.00000419 AC XY: 3 AN XY: 716644

African (AFR) AF: 0.00 AC: 0 AN: 32034

American (AMR) AF: 0.00 AC: 0 AN: 39006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24704

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 83422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 0.00000634 AC: 7 AN: 1104638

Other (OTH) AF: 0.00 AC: 0 AN: 59322

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.80	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.66		Gain of catalytic residue at A534 (P = 0.0071)
MVP		0.72
MPC		0.36
ClinPred		0.97	D
GERP RS		5.8
PromoterAI		-0.053	Neutral
Varity_R		0.77
gMVP		0.58
Mutation Taster		=34/66	disease causing

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

Other links and lift over

hg19: chr14-91110542;