14-44963023-A-T

Position:

• chr14-44963023-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000361462.7(TOGARAM1):​c.602A>T​(p.Gln201Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOGARAM1 ENST00000361462.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

Genes affected

TOGARAM1 (HGNC:19959): (TOG array regulator of axonemal microtubules 1) Predicted to enable microtubule binding activity. Predicted to be involved in organelle assembly and positive regulation of microtubule polymerization. Predicted to be located in ciliary basal body. Predicted to be active in cilium and microtubule cytoskeleton. Predicted to colocalize with microtubule. Implicated in Joubert syndrome. [provided by Alliance of Genome Resources, Apr 2022]

TOGARAM1 (HGNC:):

KLHL28 (HGNC:19741): (kelch like family member 28)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOGARAM1	NM_001308120.2	c.602A>T	p.Gln201Leu	missense_variant	1/20	ENST00000361462.7	NP_001295049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOGARAM1	ENST00000361462.7	c.602A>T	p.Gln201Leu	missense_variant	1/20	1	NM_001308120.2	ENSP00000354917.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Oct 27, 2023

The c.602A>T (p.Q201L) alteration is located in exon 1 (coding exon 1) of the FAM179B gene. This alteration results from a A to T substitution at nucleotide position 602, causing the glutamine (Q) at amino acid position 201 to be replaced by a leucine (L). 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	0.32
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.69
MutPred		0.42		Gain of ubiquitination at K197 (P = 0.0985);Gain of ubiquitination at K197 (P = 0.0985);
MVP		0.61
MPC		0.61
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.21
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-45432226;