9-27029104-GGT-AGC

Variant names:

• chr9-27029104-GGT-AGC
• NM_025103.4:c.1054_1054+2delGGTinsAGC
• IFT74 p.Gly352Ser

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_025103.4(IFT74):​c.1054_1054+2delGGTinsAGC​(p.Gly352Ser) variant causes a splice donor, missense, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G352C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFT74 NM_025103.4 splice_donor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.99
• 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)
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• primary ciliary dyskinesia

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• spermatogenic failure 58

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.5, offset of 11, new splice context is: ctgGTattt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT74	NM_025103.4	MANE Select	c.1054_1054+2delGGTinsAGC	p.Gly352Ser	splice_donor missense splice_region intron	N/A	NP_079379.2	Q96LB3-1
	IFT74	NM_001099222.3		c.1054_1054+2delGGTinsAGC	p.Gly352Ser	splice_donor missense splice_region intron	N/A	NP_001092692.1	Q96LB3-1
	IFT74	NM_001099223.3		c.1054_1054+2delGGTinsAGC	p.Gly352Ser	splice_donor missense splice_region intron	N/A	NP_001092693.1	Q96LB3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT74	ENST00000380062.10	TSL:1 MANE Select	c.1054_1054+2delGGTinsAGC	p.Gly352Ser	splice_donor missense splice_region intron	N/A	ENSP00000369402.5	Q96LB3-1
	IFT74	ENST00000429045.6	TSL:1	c.1054_1054+2delGGTinsAGC	p.Asp352Asn	splice_donor missense splice_region intron	N/A	ENSP00000393907.2	Q96LB3-2
	IFT74	ENST00000903173.1		c.1072_1072+2delGGTinsAGC	p.Gly358Ser	splice_donor missense splice_region intron	N/A	ENSP00000573232.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-27029102;