16-1564146-C-T

Position:

• chr16-1564146-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014714.4(IFT140):​c.1918G>A​(p.Asp640Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,579,900 control chromosomes in the GnomAD database, including 240 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (115 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (125 hom.)
• Consequence: IFT140 NM_014714.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.360

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]

IFT140 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031694174).
• BP6: Variant 16-1564146-C-T is Benign according to our data. Variant chr16-1564146-C-T is described in ClinVar as [Benign]. Clinvar id is 318183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1564146-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.072 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT140	NM_014714.4	c.1918G>A	p.Asp640Asn	missense_variant	17/31	ENST00000426508.7	NP_055529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT140	ENST00000426508.7	c.1918G>A	p.Asp640Asn	missense_variant	17/31	5	NM_014714.4	ENSP00000406012.2

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3296 AN: 152160 Hom.: 116 Cov.: 32

Gnomad AFR AF: 0.0745

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00568 AC: 1377 AN: 242570 Hom.: 52 AF XY: 0.00406 AC XY: 533 AN XY: 131322

Gnomad AFR exome AF: 0.0744

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000103

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.000379

Gnomad OTH exome AF: 0.00443

GnomAD4 exome AF: 0.00234 AC: 3340 AN: 1427622 Hom.: 125 Cov.: 32 AF XY: 0.00198 AC XY: 1397 AN XY: 705224

Gnomad4 AFR exome AF: 0.0770

Gnomad4 AMR exome AF: 0.00477

Gnomad4 ASJ exome AF: 0.0000394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000715

Gnomad4 FIN exome AF: 0.000359

Gnomad4 NFE exome AF: 0.000273

Gnomad4 OTH exome AF: 0.00512

GnomAD4 genome AF: 0.0216 AC: 3294 AN: 152278 Hom.: 115 Cov.: 32 AF XY: 0.0209 AC XY: 1558 AN XY: 74466

Gnomad4 AFR AF: 0.0742

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00378 Hom.: 21

Bravo AF: 0.0252

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0734 AC: 323

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00691 AC: 839

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Saldino-Mainzer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.6
DANN	Benign	0.92
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.071
Sift	Benign	0.19	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.59
MPC		0.067
ClinPred		0.00085	T
GERP RS		2.0
Varity_R		0.032
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs61742753; hg19: chr16-1614147;