chr1-83907569-T-C

Position:

• chr1-83907569-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024686.6(TTLL7):​c.1879A>G​(p.Ile627Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,461,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: TTLL7 NM_024686.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.341

Genes affected

TTLL7 (HGNC:26242): (tubulin tyrosine ligase like 7) Enables alpha-tubulin binding activity; beta-tubulin binding activity; and tubulin-glutamic acid ligase activity. Involved in protein polyglutamylation. Predicted to be located in 9+0 non-motile cilium and ciliary basal body. Predicted to be active in cilium. [provided by Alliance of Genome Resources, Apr 2022]

TTLL7 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04862991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTLL7	NM_024686.6	c.1879A>G	p.Ile627Val	missense_variant	16/21	ENST00000260505.13	NP_078962.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTLL7	ENST00000260505.13	c.1879A>G	p.Ile627Val	missense_variant	16/21	2	NM_024686.6	ENSP00000260505.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461180 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 726896

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: 0.0000414

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jun 21, 2023

The c.1879A>G (p.I627V) alteration is located in exon 16 (coding exon 15) of the TTLL7 gene. This alteration results from a A to G substitution at nucleotide position 1879, causing the isoleucine (I) at amino acid position 627 to be replaced by a valine (V). 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	0.063
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.0
DANN	Benign	0.75
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.042
Sift	Benign	0.63	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.037
MutPred		0.34		Gain of catalytic residue at I627 (P = 0.0289);
MVP		0.10
MPC		0.42
ClinPred		0.025	T
GERP RS		-5.7
Varity_R		0.046
gMVP		0.11

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

Other links and lift over

dbSNP: rs1571144350; hg19: chr1-84373252;