rs140727644

Positions:

• chr21-32604237-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021254.4(CFAP298):​c.422A>G​(p.Asp141Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000265 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: CFAP298 NM_021254.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.262043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP298	NM_021254.4	c.422A>G	p.Asp141Gly	missense_variant	4/7	ENST00000290155.8	NP_067077.1
CFAP298-TCP10L	NR_146638.2	n.556A>G		non_coding_transcript_exon_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP298	ENST00000290155.8	c.422A>G	p.Asp141Gly	missense_variant	4/7	1	NM_021254.4	ENSP00000290155	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 251490 Hom.: 0 AF XY: 0.000213 AC XY: 29 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000369

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000274 AC: 400 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.000259 AC XY: 188 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000340

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74318

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 05, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 141 of the C21orf59 protein (p.Asp141Gly). This variant is present in population databases (rs140727644, gnomAD 0.04%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 24094744). ClinVar contains an entry for this variant (Variation ID: 525246). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects C21orf59 function (PMID: 24094744). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T;.;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.089
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Uncertain	-4.3	D;D;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;.
Polyphen		0.17, 0.52	.;B;P;B;.
Vest4		0.67, 0.67, 0.70
MVP		0.15
MPC		0.22
ClinPred		0.66	D
GERP RS		3.6
Varity_R		0.38
gMVP		0.64

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: rs140727644; hg19: chr21-33976547;