chr12-110127405-A-G

Variant names:

• chr12-110127405-A-G
• rs375743897
• NM_014055.4:c.25A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001347947.2(IFT81):​c.-742A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000219 in 1,595,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: IFT81 NM_001347947.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.48
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022727698).
• BP6: Variant 12-110127405-A-G is Benign according to our data. Variant chr12-110127405-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1039058.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347947.2. 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.25A>G	p.Met9Val	missense	Exon 2 of 19	NP_054774.2
	IFT81	NM_001347947.2		c.-742A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	NP_001334876.1
	IFT81	NM_001347948.2		c.-742A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	NP_001334877.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT81	ENST00000242591.10	TSL:1 MANE Select	c.25A>G	p.Met9Val	missense	Exon 2 of 19	ENSP00000242591.5	Q8WYA0-1
	IFT81	ENST00000552912.5	TSL:1	c.25A>G	p.Met9Val	missense	Exon 2 of 19	ENSP00000449718.1	Q8WYA0-1
	IFT81	ENST00000361948.8	TSL:1	c.25A>G	p.Met9Val	missense	Exon 2 of 12	ENSP00000355372.4	Q8WYA0-3

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152200 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000351 AC: 8 AN: 227754 AF XY: 0.0000244

Gnomad AFR exome AF: 0.000559

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1443018 Hom.: 0 Cov.: 30 AF XY: 0.0000112 AC XY: 8 AN XY: 717008

African (AFR) AF: 0.000491 AC: 16 AN: 32588

American (AMR) AF: 0.00 AC: 0 AN: 40556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25348

East Asian (EAS) AF: 0.00 AC: 0 AN: 39302

South Asian (SAS) AF: 0.00 AC: 0 AN: 82354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104788

Other (OTH) AF: 0.00 AC: 0 AN: 59590

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152200 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10 AN XY: 74354

African (AFR) AF: 0.000434 AC: 18 AN: 41450

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000659 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000413 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.035
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.59
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-3.0	N
PhyloP100		6.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	2.4	N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.41
MPC		0.13
ClinPred		0.069	T
GERP RS		5.3
Varity_R		0.083
gMVP		0.42
Mutation Taster		=90/10	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: rs375743897; hg19: chr12-110565210; COSMIC: COSV99656048; COSMIC: COSV99656048;