14-75985807-G-T

Variant names:

• chr14-75985807-G-T
• rs193921095
• NM_001102564.3:c.21G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001102564.3(IFT43):​c.21G>T​(p.Leu7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L7S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFT43 NM_001102564.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.298
• Publications: 1 publications found

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]

IFT43 Gene-Disease associations (from GenCC):

• cranioectodermal dysplasia 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• short-rib thoracic dysplasia 18 with polydactyly

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• retinitis pigmentosa 81

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0945065).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001102564.3. 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
	IFT43	NM_001102564.3	MANE Select	c.21G>T	p.Leu7Phe	missense	Exon 1 of 9	NP_001096034.1
	IFT43	NM_052873.3		c.21G>T	p.Leu7Phe	missense	Exon 1 of 8	NP_443105.2
	IFT43	NM_001255995.3		c.21G>T	p.Leu7Phe	missense	Exon 1 of 4	NP_001242924.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT43	ENST00000314067.11	TSL:2 MANE Select	c.21G>T	p.Leu7Phe	missense	Exon 1 of 9	ENSP00000324177.6
	IFT43	ENST00000238628.10	TSL:1	c.21G>T	p.Leu7Phe	missense	Exon 1 of 8	ENSP00000238628.6
	IFT43	ENST00000679083.1		c.-226G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000504736.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.8
DANN	Benign	0.87
DEOGEN2	Benign	0.0099	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.30
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.15
Sift	Benign	0.27	T
Sift4G	Uncertain	0.042	D
Polyphen		0.087	B
Vest4		0.30
MutPred		0.39		Gain of loop (P = 0.0079)
MVP		0.085
MPC		0.12
ClinPred		0.30	T
GERP RS		-3.9
PromoterAI		-0.071	Neutral
Varity_R		0.047
gMVP		0.16
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs193921095; hg19: chr14-76452150; COSMIC: COSV53136860; COSMIC: COSV53136860;