rs753478409

Variant names:

• chr3-160319779-G-A
• rs753478409
• NM_020800.3:c.938C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020800.3(IFT80):​c.938C>T​(p.Thr313Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,612,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T313A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: IFT80 NM_020800.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.12
• Publications: 1 publications found

Genes affected

IFT80 (HGNC:29262): (intraflagellar transport 80) The protein encoded by this gene is part of the intraflagellar transport complex B and is necessary for the function of motile and sensory cilia. Defects in this gene are a cause of asphyxiating thoracic dystrophy 2 (ATD2). Three transcript variants encoding two different isoforms have been found for this gene.[provided by RefSeq, Jun 2010]

TRIM59-IFT80 (HGNC:56756): (TRIM59-IFT80 readthrough (NMD candidate)) This locus represents naturally occurring readthrough transcription between the neighboring TRIM59 (tripartite motif containing 59) and IFT80 (intraflagellar transport 80) genes on chromosome 3. The readthrough transcript is unlikely to produce a protein product. [provided by RefSeq, Jun 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34543633).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020800.3. 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
	IFT80	NM_020800.3	MANE Select	c.938C>T	p.Thr313Met	missense	Exon 9 of 20	NP_065851.1	Q9P2H3-1
	IFT80	NM_001190241.2		c.527C>T	p.Thr176Met	missense	Exon 10 of 21	NP_001177170.1	Q9P2H3-2
	IFT80	NM_001190242.2		c.527C>T	p.Thr176Met	missense	Exon 8 of 19	NP_001177171.1	Q9P2H3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT80	ENST00000326448.12	TSL:1 MANE Select	c.938C>T	p.Thr313Met	missense	Exon 9 of 20	ENSP00000312778.7	Q9P2H3-1
	IFT80	ENST00000483465.5	TSL:1	c.527C>T	p.Thr176Met	missense	Exon 8 of 19	ENSP00000418196.1	Q9P2H3-2
	TRIM59-IFT80	ENST00000483754.1	TSL:2	n.1451C>T		non_coding_transcript_exon	Exon 7 of 19	ENSP00000456272.1	H3BRJ5

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151838 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250988 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460718 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726666

African (AFR) AF: 0.0000598 AC: 2 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111196

Other (OTH) AF: 0.0000332 AC: 2 AN: 60326

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151838 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74152

African (AFR) AF: 0.00 AC: 0 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67912

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Jeune thoracic dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.32
Sift	Benign	0.081	T
Sift4G	Benign	0.089	T
Polyphen		0.71	P
Vest4		0.34
MutPred		0.43		Loss of methylation at K314 (P = 0.035)
MVP		0.89
MPC		0.56
ClinPred		0.89	D
GERP RS		3.8
Varity_R		0.12
gMVP		0.42
Mutation Taster		=67/33	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: rs753478409; hg19: chr3-160037567; COSMIC: COSV58449328; COSMIC: COSV58449328;