13-20615802-G-A

Variant names:

• chr13-20615802-G-A
• rs2442455
• NM_006531.5:c.1122G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006531.5(IFT88):​c.1122G>A​(p.Met374Ile) variant causes a missense change. The variant allele was found at a frequency of 0.137 in 1,587,320 control chromosomes in the GnomAD database, including 16,673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M374K) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2394 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14279 hom.)
• Consequence: IFT88 NM_006531.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.19
• Publications: 26 publications found

Genes affected

IFT88 (HGNC:20606): (intraflagellar transport 88) This gene encodes a member of the tetratrico peptide repeat (TPR) family. The encoded protein is involved in cilium biogenesis. Mutations of a similar gene in mouse can cause polycystic kidney disease. Several transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2017]

IFT88 Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 13-20615802-G-A is Benign according to our data. Variant chr13-20615802-G-A is described in ClinVar as Benign. ClinVar VariationId is 402965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006531.5. 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
	IFT88	NM_006531.5	MANE Select	c.1122G>A	p.Met374Ile	missense	Exon 14 of 26	NP_006522.2
	IFT88	NM_001318493.2		c.1149G>A	p.Met383Ile	missense	Exon 15 of 27	NP_001305422.1
	IFT88	NM_001353565.2		c.1149G>A	p.Met383Ile	missense	Exon 15 of 27	NP_001340494.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT88	ENST00000351808.10	TSL:1 MANE Select	c.1122G>A	p.Met374Ile	missense	Exon 14 of 26	ENSP00000261632.5
	IFT88	ENST00000319980.10	TSL:1	c.1149G>A	p.Met383Ile	missense	Exon 16 of 28	ENSP00000323580.6
	IFT88	ENST00000894242.1		c.1122G>A	p.Met374Ile	missense	Exon 15 of 27	ENSP00000564301.1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24962 AN: 151888 Hom.: 2394 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.126 AC: 30213 AN: 239968 AF XY: 0.125

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0857

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.134 AC: 193041 AN: 1435314 Hom.: 14279 Cov.: 27 AF XY: 0.133 AC XY: 94966 AN XY: 714680

African (AFR) AF: 0.252 AC: 8142 AN: 32320

American (AMR) AF: 0.0909 AC: 3780 AN: 41572

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4240 AN: 25600

East Asian (EAS) AF: 0.000280 AC: 11 AN: 39226

South Asian (SAS) AF: 0.0780 AC: 6471 AN: 82948

European-Finnish (FIN) AF: 0.113 AC: 5998 AN: 52860

Middle Eastern (MID) AF: 0.135 AC: 765 AN: 5672

European-Non Finnish (NFE) AF: 0.142 AC: 155739 AN: 1095634

Other (OTH) AF: 0.133 AC: 7895 AN: 59482

GnomAD4 genome AF: 0.164 AC: 24979 AN: 152006 Hom.: 2394 Cov.: 32 AF XY: 0.158 AC XY: 11715 AN XY: 74318

African (AFR) AF: 0.252 AC: 10433 AN: 41406

American (AMR) AF: 0.125 AC: 1907 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 583 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0635 AC: 305 AN: 4806

European-Finnish (FIN) AF: 0.108 AC: 1145 AN: 10572

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10150 AN: 67982

Other (OTH) AF: 0.143 AC: 302 AN: 2112

Alfa AF: 0.151 Hom.: 6668

Bravo AF: 0.170

TwinsUK AF: 0.132 AC: 490

ALSPAC AF: 0.148 AC: 571

ESP6500AA AF: 0.248 AC: 1094

ESP6500EA AF: 0.147 AC: 1264

ExAC AF: 0.132 AC: 15962

Asia WGS AF: 0.0400 AC: 140 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.090
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.011
Sift	Benign	0.18	T
Sift4G	Benign	0.19	T
Polyphen		0.023	B
Vest4		0.17
MutPred		0.34		Loss of disorder (P = 0.0696)
MPC		0.048
ClinPred		0.0065	T
GERP RS		4.7
Varity_R		0.15
gMVP		0.45
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -9

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

Other links and lift over

dbSNP: rs2442455; hg19: chr13-21189941; COSMIC: COSV60673403; COSMIC: COSV60673403;