rs11552421

Positions:

• chr11-118559804-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001168618.2(IFT46):​c.26G>A​(p.Cys9Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,610,856 control chromosomes in the GnomAD database, including 24,379 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.17 (2773 hom., cov: 31)
  • Exomes 𝑓: 0.15 (21606 hom.)
• Consequence: IFT46 NM_001168618.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.130

Genes affected

IFT46 (HGNC:26146): (intraflagellar transport 46) Predicted to enable protein C-terminus binding activity. Predicted to be involved in cilium assembly; intraciliary transport; and protein stabilization. Predicted to act upstream of or within smoothened signaling pathway. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2430549E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT46	NM_001168618.2	c.26G>A	p.Cys9Tyr	missense_variant	3/12	ENST00000264021.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT46	ENST00000264021.8	c.26G>A	p.Cys9Tyr	missense_variant	3/12	1	NM_001168618.2	P1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25889 AN: 152052 Hom.: 2772 Cov.: 31

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.159

GnomAD3 exomes AF: 0.183 AC: 45997 AN: 250934 Hom.: 6026 AF XY: 0.191 AC XY: 25917 AN XY: 135602

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.0689

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.510

Gnomad SAS exome AF: 0.327

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.153 AC: 223390 AN: 1458686 Hom.: 21606 Cov.: 30 AF XY: 0.159 AC XY: 115096 AN XY: 725700

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.0711

Gnomad4 ASJ exome AF: 0.148

Gnomad4 EAS exome AF: 0.466

Gnomad4 SAS exome AF: 0.325

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.170 AC: 25910 AN: 152170 Hom.: 2773 Cov.: 31 AF XY: 0.173 AC XY: 12884 AN XY: 74392

Gnomad4 AFR AF: 0.203

Gnomad4 AMR AF: 0.0999

Gnomad4 ASJ AF: 0.146

Gnomad4 EAS AF: 0.507

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.163

Alfa AF: 0.145 Hom.: 4508

Bravo AF: 0.164

TwinsUK AF: 0.135 AC: 501

ALSPAC AF: 0.137 AC: 527

ESP6500AA AF: 0.199 AC: 874

ESP6500EA AF: 0.132 AC: 1138

ExAC AF: 0.186 AC: 22644

Asia WGS AF: 0.428 AC: 1488 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.135

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.74
DEOGEN2	Benign	0.0011	T;.;.;.;.;.;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.17	T;T;T;T;T;T;T;T
MetaRNN	Benign	0.00012	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.4	N;N;.;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	1.8	N;N;N;N;N;N;N;N
REVEL	Benign	0.053
Sift	Benign	1.0	T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;.;.;T;.;.
Polyphen		0.0	B;B;B;.;.;.;.;.
Vest4		0.12
MPC		0.30
ClinPred		0.00098	T
GERP RS		1.5
Varity_R		0.032
gMVP		0.043

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11552421; hg19: chr11-118430519; COSMIC: COSV50594316; COSMIC: COSV50594316;