rs138178722

Positions:

• chr21-32612167-T-G

Variant summary

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

The NM_021254.4(CFAP298):​c.77A>C​(p.Glu26Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,597,998 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (17 hom.)
• Consequence: CFAP298 NM_021254.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.42

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]

CFAP298-TCP10L (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008645952).
• BP6: Variant 21-32612167-T-G is Benign according to our data. Variant chr21-32612167-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 241379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00233 (355/152264) while in subpopulation AMR AF= 0.00908 (139/15304). AF 95% confidence interval is 0.00785. There are 2 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP298	NM_021254.4	c.77A>C	p.Glu26Ala	missense_variant	1/7	ENST00000290155.8	NP_067077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP298	ENST00000290155.8	c.77A>C	p.Glu26Ala	missense_variant	1/7	1	NM_021254.4	ENSP00000290155.3
CFAP298-TCP10L	ENST00000673807.1	c.77A>C	p.Glu26Ala	missense_variant	1/8			ENSP00000501088.1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152146 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00909

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.00252 AC: 551 AN: 218886 Hom.: 3 AF XY: 0.00259 AC XY: 307 AN XY: 118756

Gnomad AFR exome AF: 0.000459

Gnomad AMR exome AF: 0.00625

Gnomad ASJ exome AF: 0.00760

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00187

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00601

GnomAD4 exome AF: 0.00181 AC: 2618 AN: 1445734 Hom.: 17 Cov.: 31 AF XY: 0.00192 AC XY: 1376 AN XY: 717476

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00649

Gnomad4 ASJ exome AF: 0.00728

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00233

Gnomad4 FIN exome AF: 0.000507

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00236 AC XY: 176 AN XY: 74430

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00908

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00225 Hom.: 3

Bravo AF: 0.00277

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00212 AC: 257

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CFAP298: BP4, BS2; CFAP298-TCP10L: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.079	.;T;.;T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.69	T;T;T;T;T
MetaRNN	Benign	0.0086	T;T;T;T;T
MetaSVM	Benign	-0.95	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D
REVEL	Benign	0.074
Sift	Benign	0.25	T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;.
Polyphen		0.0040, 0.011, 0.0020	.;B;B;B;.
Vest4		0.20, 0.15, 0.12
MVP		0.14
MPC		0.15
ClinPred		0.030	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.35
gMVP		0.38

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: rs138178722; hg19: chr21-33984477;