3-160268478-G-T

Variant names:

• chr3-160268478-G-T
• rs201820395
• NM_020800.3:c.2158C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000326448.12(IFT80):​c.2158C>A​(p.Gln720Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000211 in 1,613,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: IFT80 ENST00000326448.12 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 7.03
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07509744).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000326448.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT80	NM_020800.3	MANE Select	c.2158C>A	p.Gln720Lys	missense	Exon 19 of 20	NP_065851.1
	IFT80	NM_001190241.2		c.1747C>A	p.Gln583Lys	missense	Exon 20 of 21	NP_001177170.1
	IFT80	NM_001190242.2		c.1747C>A	p.Gln583Lys	missense	Exon 18 of 19	NP_001177171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT80	ENST00000326448.12	TSL:1 MANE Select	c.2158C>A	p.Gln720Lys	missense	Exon 19 of 20	ENSP00000312778.7
	IFT80	ENST00000483465.5	TSL:1	c.1747C>A	p.Gln583Lys	missense	Exon 18 of 19	ENSP00000418196.1
	TRIM59-IFT80	ENST00000483754.1	TSL:2	n.2671C>A		non_coding_transcript_exon	Exon 17 of 19	ENSP00000456272.1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.000265

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000223 AC: 56 AN: 251092 AF XY: 0.000199

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000211 AC: 308 AN: 1461000 Hom.: 0 Cov.: 30 AF XY: 0.000213 AC XY: 155 AN XY: 726848

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.000559 AC: 25 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86224

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5748

European-Non Finnish (NFE) AF: 0.000229 AC: 255 AN: 1111344

Other (OTH) AF: 0.000331 AC: 20 AN: 60358

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74444

African (AFR) AF: 0.0000963 AC: 4 AN: 41552

American (AMR) AF: 0.000588 AC: 9 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000249

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Asphyxiating thoracic dystrophy 2 (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	Jeune thoracic dystrophy (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.0028
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.18
Sift	Benign	0.25	T
Sift4G	Benign	0.48	T
Polyphen		0.0090	B
Vest4		0.45
MVP		0.81
MPC		0.20
ClinPred		0.048	T
GERP RS		5.0
Varity_R		0.23
gMVP		0.73
Mutation Taster		=86/14	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: rs201820395; hg19: chr3-159986266; COSMIC: COSV58452491;