chr21-32603155-A-G

Variant names:

• chr21-32603155-A-G
• rs372359409
• ENST00000382549.8:c.672T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_021254.4(CFAP298):​c.666+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000923 in 1,614,172 control chromosomes in the GnomAD database, including 6 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (3 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (3 hom.)
• Consequence: CFAP298 NM_021254.4 splice_region, intron
• Scores: Splicing: ADA: 0.03716
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.347
• Publications: 0 publications found

Genes affected

CFAP298 (HGNC:1301): (cilia and flagella associated protein 298) This gene encodes a protein that plays a critical role in dynein arm assembly and motile cilia function. Mutations in this gene result in primary ciliary dyskinesia. Naturally occuring readthrough transcription occurs from this locus to the downstream t-complex 10 like (TCP10L) gene. [provided by RefSeq, Apr 2017]

CFAP298-TCP10L (HGNC:54636): (CFAP298-TCP10L readthrough) This locus represents naturally occurring readthrough transcription between the neighboring chromosome 21 open reading frame 59 (C21orf59) and TCP10L (t-complex 10 like) genes on chromosome 21. Readthrough transcripts may encode a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000862 (126/1461812) while in subpopulation MID AF = 0.00433 (25/5768). AF 95% confidence interval is 0.00301. There are 3 homozygotes in GnomAdExome4. There are 74 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021254.4. 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
	CFAP298	NM_021254.4	MANE Select	c.666+6T>C		splice_region intron	N/A	NP_067077.1	P57076
	CFAP298	NM_001350335.2		c.672T>C	p.Ser224Ser	synonymous	Exon 5 of 5	NP_001337264.1	D3DSE6
	CFAP298-TCP10L	NM_001350338.2		c.666+6T>C		splice_region intron	N/A	NP_001337267.1	A0A669KAY3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP298	ENST00000382549.8	TSL:1	c.672T>C	p.Ser224Ser	synonymous	Exon 5 of 5	ENSP00000371989.4	D3DSE6
	CFAP298	ENST00000290155.8	TSL:1 MANE Select	c.666+6T>C		splice_region intron	N/A	ENSP00000290155.3	P57076
	CFAP298-TCP10L	ENST00000673807.1		c.666+6T>C		splice_region intron	N/A	ENSP00000501088.1	A0A669KAY3

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152242 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000954 AC: 24 AN: 251452 AF XY: 0.000110

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: 0.000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000862 AC: 126 AN: 1461812 Hom.: 3 Cov.: 32 AF XY: 0.000102 AC XY: 74 AN XY: 727206

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.0000737 AC: 82 AN: 1111936

Other (OTH) AF: 0.000215 AC: 13 AN: 60394

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152360 Hom.: 3 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74508

African (AFR) AF: 0.0000481 AC: 2 AN: 41584

American (AMR) AF: 0.000327 AC: 5 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

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

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000718

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.7
DANN	Benign	0.78
PhyloP100		0.35
PromoterAI		-0.21	Neutral
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.037
dbscSNV1_RF	Benign	0.55
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

Other links and lift over

dbSNP: rs372359409; hg19: chr21-33975465;