chr12-110180532-ACTT-A

Variant names:

• chr12-110180532-ACTT-A
• rs1555266475
• NM_014055.4:c.1303_1305delCTT

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_014055.4(IFT81):​c.1303_1305delCTT​(p.Leu435del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000481 in 1,455,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L435L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: IFT81 NM_014055.4 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 7.02
• Publications: 0 publications found

Genes affected

IFT81 (HGNC:14313): (intraflagellar transport 81) The protein encoded by this gene, together with IFT74, forms a tubulin-binding module of intraflagellar transport complex B. This module is involved in transport of tubulin within the cilium, and the encoded protein is required for ciliogenesis. Mutations in this gene are a cause of short-rib polydactyly syndromes. [provided by RefSeq, Dec 2016]

IFT81 Gene-Disease associations (from GenCC):

• short-rib thoracic dysplasia 19 with or without polydactyly

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_014055.4. Strenght limited to Supporting due to length of the change: 1aa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014055.4. 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
	IFT81	NM_014055.4	MANE Select	c.1303_1305delCTT	p.Leu435del	conservative_inframe_deletion	Exon 12 of 19	NP_054774.2
	IFT81	NM_001143779.2		c.1303_1305delCTT	p.Leu435del	conservative_inframe_deletion	Exon 12 of 19	NP_001137251.1	Q8WYA0-1
	IFT81	NM_001347947.2		c.373_375delCTT	p.Leu125del	conservative_inframe_deletion	Exon 11 of 18	NP_001334876.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT81	ENST00000242591.10	TSL:1 MANE Select	c.1303_1305delCTT	p.Leu435del	conservative_inframe_deletion	Exon 12 of 19	ENSP00000242591.5	Q8WYA0-1
	IFT81	ENST00000552912.5	TSL:1	c.1303_1305delCTT	p.Leu435del	conservative_inframe_deletion	Exon 12 of 19	ENSP00000449718.1	Q8WYA0-1
	IFT81	ENST00000969905.1		c.1351_1353delCTT	p.Leu451del	conservative_inframe_deletion	Exon 13 of 20	ENSP00000639964.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1455762 Hom.: 0 AF XY: 0.00000828 AC XY: 6 AN XY: 724236

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.00 AC: 0 AN: 85614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000632 AC: 7 AN: 1107624

Other (OTH) AF: 0.00 AC: 0 AN: 60042

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Short-rib thoracic dysplasia 19 with or without polydactyly (2)
1	-	-	Short rib-polydactyly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=65/35	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: rs1555266475; hg19: chr12-110618337;