chr2-27447640-G-A

Position:

• chr2-27447640-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015662.3(IFT172):​c.4540-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00445 in 1,614,120 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (56 hom.)
• Consequence: IFT172 NM_015662.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004300
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0830

Genes affected

IFT172 (HGNC:30391): (intraflagellar transport 172) This gene encodes a subunit of the intraflagellar transport subcomplex IFT-B. Subcomplexes IFT-A and IFT-B are necessary for ciliary assembly and maintenance. Mutations in this gene have been associated with skeletal ciliopathies, with or without polydactyly, such as such short-rib thoracic dysplasias 1, 9 or 10. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-27447640-G-A is Benign according to our data. Variant chr2-27447640-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 379446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27447640-G-A is described in Lovd as [Benign]. Variant chr2-27447640-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00342 (521/152346) while in subpopulation NFE AF= 0.00354 (241/68026). AF 95% confidence interval is 0.00318. There are 8 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT172	NM_015662.3	c.4540-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000260570.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT172	ENST00000260570.8	c.4540-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015662.3	P1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 521 AN: 152228 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.0640

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00431 AC: 1084 AN: 251364 Hom.: 16 AF XY: 0.00406 AC XY: 552 AN XY: 135858

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0595

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000695

Gnomad NFE exome AF: 0.00362

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00456 AC: 6666 AN: 1461774 Hom.: 56 Cov.: 31 AF XY: 0.00445 AC XY: 3239 AN XY: 727202

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0559

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000787

Gnomad4 NFE exome AF: 0.00428

Gnomad4 OTH exome AF: 0.00623

GnomAD4 genome AF: 0.00342 AC: 521 AN: 152346 Hom.: 8 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74492

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.0640

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00781 Hom.: 6

Bravo AF: 0.00318

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00367

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	IFT172: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2019	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Short-rib thoracic dysplasia 10 with or without polydactyly;C4225342:Retinitis pigmentosa 71 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.5
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		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: rs146140583; hg19: chr2-27670507; COSMIC: COSV53135815; COSMIC: COSV53135815;