chr14-44962533-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001308120.2(TOGARAM1):​c.112G>A​(p.Val38Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,502 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: 0.0000021 (0 hom.)
• Consequence: TOGARAM1 NM_001308120.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.443
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031391263).

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.112G>A	p.Val38Ile	missense	Exon 1 of 20	NP_001295049.1	G3XAE9
	TOGARAM1	NM_015091.4		c.112G>A	p.Val38Ile	missense	Exon 1 of 19	NP_055906.2	Q9Y4F4-1
	TOGARAM1	NR_131765.2		n.344G>A		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.112G>A	p.Val38Ile	missense	Exon 1 of 20	ENSP00000354917.2	G3XAE9
	TOGARAM1	ENST00000361577.7	TSL:1	c.112G>A	p.Val38Ile	missense	Exon 1 of 19	ENSP00000355045.3	Q9Y4F4-1
	TOGARAM1	ENST00000555607.1	TSL:1	n.320G>A		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461502 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111910

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

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	0.089
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.5
DANN	Benign	0.94
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.44
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.088
Sift	Benign	0.14	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.14		Loss of sheet (P = 0.1158)
MVP		0.040
MPC		0.13
ClinPred		0.084	T
GERP RS		-1.2
PromoterAI		0.0066	Neutral
Varity_R		0.036
gMVP		0.11
Mutation Taster		=96/4	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: rs1239776657; hg19: chr14-45431736;