3-108162648-C-G

Variant names:

• chr3-108162648-C-G
• rs200995912
• NM_018010.4:c.1119G>C

Variant summary

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

The NM_018010.4(IFT57):​c.1119G>C​(p.Leu373Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,602 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IFT57 NM_018010.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.944
• Publications: 0 publications found

Genes affected

IFT57 (HGNC:17367): (intraflagellar transport 57) Predicted to enable DNA binding activity. Acts upstream of or within activation of cysteine-type endopeptidase activity involved in apoptotic process; apoptotic process; and regulation of apoptotic process. Predicted to be located in ciliary basal body. Predicted to be part of axoneme and intraciliary transport particle B. Predicted to be active in Golgi apparatus; centrosome; and cilium. Implicated in orofaciodigital syndrome. [provided by Alliance of Genome Resources, Apr 2022]

IFT57 Gene-Disease associations (from GenCC):

• orofaciodigital syndrome 18

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018010.4. 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
	IFT57	NM_018010.4	MANE Select	c.1119G>C	p.Leu373Phe	missense	Exon 11 of 11	NP_060480.1	Q9NWB7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT57	ENST00000264538.4	TSL:1 MANE Select	c.1119G>C	p.Leu373Phe	missense	Exon 11 of 11	ENSP00000264538.3	Q9NWB7
	IFT57	ENST00000878338.1		c.1230G>C	p.Leu410Phe	missense	Exon 12 of 12	ENSP00000548397.1
	IFT57	ENST00000939116.1		c.1212G>C	p.Leu404Phe	missense	Exon 11 of 11	ENSP00000609175.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442602 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 716606

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32726

American (AMR) AF: 0.00 AC: 0 AN: 42134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25374

East Asian (EAS) AF: 0.00 AC: 0 AN: 39294

South Asian (SAS) AF: 0.00 AC: 0 AN: 83168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101706

Other (OTH) AF: 0.00 AC: 0 AN: 59560

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.94
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.75		Gain of methylation at K375 (P = 0.0971)
MVP		0.85
MPC		0.81
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.24
gMVP		0.28
Mutation Taster		=35/65	disease causing

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: rs200995912; hg19: chr3-107881495;