NM_001177701.3:c.503C>T

Variant names:

• chr22-36758369-G-A
• rs118095726
• NM_001177701.3:c.503C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_001177701.3(IFT27):​c.503C>T​(p.Ala168Val) variant causes a missense change. The variant allele was found at a frequency of 0.000804 in 1,614,170 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (1 hom.)
• Consequence: IFT27 NM_001177701.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 7.08
• Publications: 3 publications found

Genes affected

IFT27 (HGNC:18626): (intraflagellar transport 27) This gene encodes a GTP-binding protein that is a core component of the intraflagellar transport complex B. Characterization of the similar Chlamydomonas protein indicates a function in cell cycle control. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2012]

CACNG2-DT (HGNC:55682): (CACNG2 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 22-36758369-G-A is Benign according to our data. Variant chr22-36758369-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 841662.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000617 (94/152336) while in subpopulation NFE AF = 0.000853 (58/68030). AF 95% confidence interval is 0.000677. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177701.3. 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
	IFT27	NM_001177701.3	MANE Select	c.503C>T	p.Ala168Val	missense	Exon 7 of 7	NP_001171172.1	Q9BW83-1
	IFT27	NM_001363003.2		c.503C>T	p.Ala168Val	missense	Exon 8 of 8	NP_001349932.1	Q9BW83-1
	IFT27	NM_006860.5		c.500C>T	p.Ala167Val	missense	Exon 7 of 7	NP_006851.1	Q9BW83-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT27	ENST00000433985.7	TSL:1 MANE Select	c.503C>T	p.Ala168Val	missense	Exon 7 of 7	ENSP00000393541.2	Q9BW83-1
	IFT27	ENST00000340630.9	TSL:1	c.500C>T	p.Ala167Val	missense	Exon 7 of 7	ENSP00000343593.5	Q9BW83-2
	IFT27	ENST00000916904.1		c.617C>T	p.Ala206Val	missense	Exon 8 of 8	ENSP00000586963.1

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000852

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000553 AC: 139 AN: 251496 AF XY: 0.000486

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000958

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000823 AC: 1203 AN: 1461834 Hom.: 1 Cov.: 30 AF XY: 0.000766 AC XY: 557 AN XY: 727232

African (AFR) AF: 0.000986 AC: 33 AN: 33478

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.000993 AC: 1104 AN: 1111994

Other (OTH) AF: 0.000629 AC: 38 AN: 60392

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74488

African (AFR) AF: 0.000577 AC: 24 AN: 41574

American (AMR) AF: 0.000653 AC: 10 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000890 Hom.: 0

Bravo AF: 0.000589

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000610 AC: 74

EpiCase AF: 0.000600

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	IFT27-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.9	L
PhyloP100		7.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.75
MVP		0.72
MPC		0.49
ClinPred		0.083	T
GERP RS		5.4
Varity_R		0.74
gMVP		0.48
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs118095726; hg19: chr22-37154413;