9-27029104-G-C

Variant names:

• chr9-27029104-G-C
• rs759662469
• NM_025103.4:c.1054G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_025103.4(IFT74):​c.1054G>C​(p.Gly352Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000694 in 1,440,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IFT74 NM_025103.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• 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)
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-27029104-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 446684.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, 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.1054G>C	p.Gly352Arg	missense splice_region	Exon 13 of 20	NP_079379.2
	IFT74	NM_001099222.3		c.1054G>C	p.Gly352Arg	missense splice_region	Exon 13 of 20	NP_001092692.1
	IFT74	NM_001099223.3		c.1054G>C	p.Gly352Arg	missense splice_region	Exon 13 of 20	NP_001092693.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT74	ENST00000380062.10	TSL:1 MANE Select	c.1054G>C	p.Gly352Arg	missense splice_region	Exon 13 of 20	ENSP00000369402.5
	IFT74	ENST00000429045.6	TSL:1	c.1054G>C	p.Asp352His	missense splice_region	Exon 13 of 14	ENSP00000393907.2
	IFT74	ENST00000433700.5	TSL:5	c.1054G>C	p.Gly352Arg	missense splice_region	Exon 13 of 20	ENSP00000389224.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440248 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 716678

African (AFR) AF: 0.00 AC: 0 AN: 32462

American (AMR) AF: 0.00 AC: 0 AN: 41278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25654

East Asian (EAS) AF: 0.00 AC: 0 AN: 39304

South Asian (SAS) AF: 0.00 AC: 0 AN: 82442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100512

Other (OTH) AF: 0.0000168 AC: 1 AN: 59602

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.94	T
PhyloP100		5.0
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.077
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.019	D
Polyphen		0.13	B
Vest4		0.19
MutPred		0.17		Loss of disorder (P = 0.1728)
MVP		0.72
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.60
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 11
DS_DL_spliceai		0.81		Position offset: 0

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

Other links and lift over

dbSNP: rs759662469; hg19: chr9-27029102;