rs779007169

Positions:

• chr16-1520177-C-G
• chr16-1520177-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_014714.4(IFT140):​c.3827G>C​(p.Gly1276Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1276E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: IFT140 NM_014714.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.11

Genes affected

IFT140 (HGNC:29077): (intraflagellar transport 140) This gene encodes one of the subunits of the intraflagellar transport (IFT) complex A. Intraflagellar transport is involved in the genesis, resorption and signaling of primary cilia. The primary cilium is a microtubule-based sensory organelle at the surface of most quiescent mammalian cells, that receives signals from its environment, such as the flow of fluid, light or odors, and transduces those signals to the nucleus. Loss of the corresponding protein in mouse results in renal cystic disease. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-1520177-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT140	NM_014714.4	c.3827G>C	p.Gly1276Ala	missense_variant	28/31	ENST00000426508.7	NP_055529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT140	ENST00000426508.7	c.3827G>C	p.Gly1276Ala	missense_variant	28/31	5	NM_014714.4	ENSP00000406012	P1
IFT140	ENST00000361339.9	c.1409G>C	p.Gly470Ala	missense_variant	10/13	1		ENSP00000354895
IFT140	ENST00000565298.5	n.3651G>C		non_coding_transcript_exon_variant	16/19	2
IFT140	ENST00000397417.6	c.*2265G>C		3_prime_UTR_variant, NMD_transcript_variant	21/24	5		ENSP00000380562

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.35
Sift	Benign	0.45	T;D
Sift4G	Benign	0.36	T;T
Polyphen		0.99	.;D
Vest4		0.60
MutPred		0.60		.;Gain of helix (P = 0.132);
MVP		0.41
MPC		0.28
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.77
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs779007169; hg19: chr16-1570178;