chr3-108162558-T-G

Variant names:

• chr3-108162558-T-G
• rs371511443
• NM_018010.4:c.1209A>C

Variant summary

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

The NM_018010.4(IFT57):​c.1209A>C​(p.Gln403His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,460,528 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. Q403Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: IFT57 NM_018010.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.223
• 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.1209A>C	p.Gln403His	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.1209A>C	p.Gln403His	missense	Exon 11 of 11	ENSP00000264538.3	Q9NWB7
	IFT57	ENST00000878338.1		c.1320A>C	p.Gln440His	missense	Exon 12 of 12	ENSP00000548397.1
	IFT57	ENST00000939116.1		c.1302A>C	p.Gln434His	missense	Exon 11 of 11	ENSP00000609175.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250704 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1460528 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 726554

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111118

Other (OTH) AF: 0.0000166 AC: 1 AN: 60324

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.0024	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	3.4
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.0079	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.22
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.25
Sift	Benign	0.11	T
Sift4G	Benign	0.32	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.20		Loss of MoRF binding (P = 0.1006)
MVP		0.36
MPC		0.35
ClinPred		0.56	D
GERP RS		-5.8
Varity_R		0.24
gMVP		0.40
Mutation Taster		=86/14	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: rs371511443; hg19: chr3-107881405;