rs769724508

chr14-75985788-T-Achr14-75985788-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_001102564.3(IFT43):c.2T>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000434 in 1,613,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: IFT43 NM_001102564.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.73

Genes affected

IFT43 (HGNC:29669): (intraflagellar transport 43) This gene encodes a subunit of the intraflagellar transport complex A (IFT-A). IFT-A is a multiprotein complex that plays an important role in cilia assembly and maintenance by mediating retrograde ciliary transport. Mutations in this gene are a cause of cranioectodermal dysplasia-3 (CED3), also known as Sensenbrenner syndrome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001102564.3 (IFT43) was described as [Pathogenic] in ClinVar as 1452113
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-75985788-T-A is Pathogenic according to our data. Variant chr14-75985788-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 488649.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-75985788-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT43	NM_001102564.3	c.2T>A	p.Met1?	start_lost	1/9	ENST00000314067.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT43	ENST00000314067.11	c.2T>A	p.Met1?	start_lost	1/9	2	NM_001102564.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74272

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 18, 2019

For these reasons, this variant has been classified as Pathogenic. Disruption of the initiator codon has been observed to segregate with short rib polydactyly syndrome and cranioectodermal dysplasia in families (PMID: 28400947, 21378380). ClinVar contains an entry for this variant (Variation ID: 488649). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the IFT43 mRNA. The next in-frame methionine is located at codon 22. -

Short-rib thoracic dysplasia 18 with polydactyly Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 05, 2018

- -

Short rib-polydactyly syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Mar 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	23
Dann	Benign	0.96
DEOGEN2	Benign	0.017	T;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-1.6	N;N;D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.96
MutPred		0.97		Gain of ubiquitination at M1 (P = 0.0066);Gain of ubiquitination at M1 (P = 0.0066);Gain of ubiquitination at M1 (P = 0.0066);
MVP		0.56
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.93
gMVP		0.53

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: rs769724508; hg19: chr14-76452131;