rs551515830

Variant names:

• chr9-26962088-G-GT
• rs551515830
• NM_025103.4:c.120+2dupT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_025103.4(IFT74):​c.120+2dupT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000763 in 1,613,954 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (1 hom.)
• Consequence: IFT74 NM_025103.4 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:3
• Conservation: PhyloP100: 3.99
• Publications: 0 publications found

Genes affected

IFT74 (HGNC:21424): (intraflagellar transport 74) This gene encodes a core intraflagellar transport (IFT) protein which belongs to a multi-protein complex involved in the transport of ciliary proteins along axonemal microtubules. IFT proteins are found at the base of the cilium as well as inside the cilium, where they assemble into long arrays between the ciliary base and tip. This protein, together with intraflagellar transport protein 81, binds and transports tubulin within cilia and is required for ciliogenesis. Naturally occurring mutations in this gene are associated with amyotrophic lateral sclerosis--frontotemporal dementia and Bardet-Biedl Syndrome. [provided by RefSeq, Mar 2017]

IFT74 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 22

  Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 58

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025103.4. 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
	IFT74	NM_025103.4	MANE Select	c.120+2dupT		splice_region intron	N/A	NP_079379.2
	IFT74	NM_001099222.3		c.120+2dupT		splice_region intron	N/A	NP_001092692.1
	IFT74	NM_001099223.3		c.120+2dupT		splice_region intron	N/A	NP_001092693.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT74	ENST00000380062.10	TSL:1 MANE Select	c.120+1_120+2insT		splice_donor intron	N/A	ENSP00000369402.5
	IFT74	ENST00000429045.6	TSL:1	c.120+1_120+2insT		splice_donor intron	N/A	ENSP00000393907.2
	IFT74	ENST00000433700.5	TSL:5	c.120+1_120+2insT		splice_donor intron	N/A	ENSP00000389224.1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000808

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000325 AC: 81 AN: 249506 AF XY: 0.000295

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000671

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000796 AC: 1163 AN: 1461748 Hom.: 1 Cov.: 31 AF XY: 0.000756 AC XY: 550 AN XY: 727174

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00102 AC: 1131 AN: 1111928

Other (OTH) AF: 0.000348 AC: 21 AN: 60382

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74362

African (AFR) AF: 0.000241 AC: 10 AN: 41458

American (AMR) AF: 0.000196 AC: 3 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000808 AC: 55 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000736 Hom.: 0

Bravo AF: 0.000434

EpiCase AF: 0.000872

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Short-rib thoracic dysplasia 6 with or without polydactyly (2)
-	1	-	IFT74-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.73		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs551515830; hg19: chr9-26962086;