14-44962533-G-T

Variant names:

• chr14-44962533-G-T
• rs1239776657
• NM_001308120.2:c.112G>T

Variant summary

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

The NM_001308120.2(TOGARAM1):​c.112G>T​(p.Val38Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TOGARAM1 NM_001308120.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.443

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

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=0.047587693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOGARAM1	NM_001308120.2	c.112G>T	p.Val38Phe	missense_variant	Exon 1 of 20	ENST00000361462.7	NP_001295049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOGARAM1	ENST00000361462.7	c.112G>T	p.Val38Phe	missense_variant	Exon 1 of 20	1	NM_001308120.2	ENSP00000354917.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461502 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000333 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.0
DANN	Benign	0.95
DEOGEN2	Benign	0.0077	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.079
Sift	Benign	0.042	D;.
Sift4G	Benign	0.14	T;T
Polyphen		0.091	B;B
Vest4		0.16
MVP		0.099
MPC		0.25
ClinPred		0.11	T
GERP RS		-1.2
Varity_R		0.061
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs1239776657; hg19: chr14-45431736;