rs1885198804

Variant names:

• chr14-44962429-C-T
• rs1885198804
• NM_001308120.2:c.8C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001308120.2(TOGARAM1):​c.8C>T​(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,407,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A3A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TOGARAM1 NM_001308120.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08217633).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308120.2. 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
	TOGARAM1	NM_001308120.2	MANE Select	c.8C>T	p.Ala3Val	missense	Exon 1 of 20	NP_001295049.1	G3XAE9
	TOGARAM1	NM_015091.4		c.8C>T	p.Ala3Val	missense	Exon 1 of 19	NP_055906.2	Q9Y4F4-1
	TOGARAM1	NR_131765.2		n.240C>T		non_coding_transcript_exon	Exon 1 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOGARAM1	ENST00000361462.7	TSL:1 MANE Select	c.8C>T	p.Ala3Val	missense	Exon 1 of 20	ENSP00000354917.2	G3XAE9
	TOGARAM1	ENST00000361577.7	TSL:1	c.8C>T	p.Ala3Val	missense	Exon 1 of 19	ENSP00000355045.3	Q9Y4F4-1
	TOGARAM1	ENST00000555607.1	TSL:1	n.216C>T		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1407336 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 695408

African (AFR) AF: 0.00 AC: 0 AN: 32056

American (AMR) AF: 0.00 AC: 0 AN: 38638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22508

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39300

South Asian (SAS) AF: 0.00 AC: 0 AN: 78564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5412

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086940

Other (OTH) AF: 0.00 AC: 0 AN: 58074

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.33
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.9
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.029
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.21		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.18
MPC		0.16
ClinPred		0.87	D
GERP RS		4.0
PromoterAI		-0.14	Neutral
Varity_R		0.094
gMVP		0.38
Mutation Taster		=79/21	polymorphism

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

dbSNP: rs1885198804; hg19: chr14-45431632;