chr3-108162648-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_018010.4(IFT57):​c.1119G>T​(p.Leu373Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,594,838 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: IFT57 NM_018010.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.944
• Publications: 4 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3783087).

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>T	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>T	p.Leu373Phe	missense	Exon 11 of 11	ENSP00000264538.3	Q9NWB7
	IFT57	ENST00000878338.1		c.1230G>T	p.Leu410Phe	missense	Exon 12 of 12	ENSP00000548397.1
	IFT57	ENST00000939116.1		c.1212G>T	p.Leu404Phe	missense	Exon 11 of 11	ENSP00000609175.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000151 AC: 36 AN: 238334 AF XY: 0.000132

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.0000947

Gnomad ASJ exome AF: 0.000210

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000234

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000207 AC: 298 AN: 1442600 Hom.: 0 Cov.: 29 AF XY: 0.000193 AC XY: 138 AN XY: 716606

African (AFR) AF: 0.0000306 AC: 1 AN: 32726

American (AMR) AF: 0.000119 AC: 5 AN: 42134

Ashkenazi Jewish (ASJ) AF: 0.0000788 AC: 2 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: 0.0000944 AC: 5 AN: 52984

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5656

European-Non Finnish (NFE) AF: 0.000254 AC: 280 AN: 1101704

Other (OTH) AF: 0.0000672 AC: 4 AN: 59560

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74434

African (AFR) AF: 0.0000481 AC: 2 AN: 41554

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000197 Hom.: 1

Bravo AF: 0.000121

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000206 AC: 25

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.38	T
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	0.38
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		0.24	T
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;