ENST00000382549.8:c.672T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP7 BS1_Supporting BS2

The ENST00000382549.8(CFAP298):​c.672T>C​(p.Ser224Ser) variant causes a synonymous 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. 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 ENST00000382549.8 synonymous
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP7: Synonymous conserved (PhyloP=0.347 with no splicing effect.
• 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. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000382549.8. 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;