chr10-132810415-T-C

Variant names:

• chr10-132810415-T-C
• rs753574836
• NM_001200049.3:c.7658A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001200049.3(CFAP46):​c.7658A>G​(p.Glu2553Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CFAP46 NM_001200049.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.68
• Publications: 0 publications found

Genes affected

CFAP46 (HGNC:25247): (cilia and flagella associated protein 46) Predicted to be involved in axoneme assembly. Predicted to be located in axoneme. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0828796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP46	NM_001200049.3	c.7658A>G	p.Glu2553Gly	missense_variant	Exon 57 of 58	ENST00000368586.10	NP_001186978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP46	ENST00000368586.10	c.7658A>G	p.Glu2553Gly	missense_variant	Exon 57 of 58	5	NM_001200049.3	ENSP00000357575.4
CFAP46	ENST00000639072.2	c.7795A>G	p.Asn2599Asp	missense_variant	Exon 58 of 59	5		ENSP00000491877.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248320 AF XY: 0.0000223

Gnomad AFR exome AF: 0.000123

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: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461048 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726834

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52696

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111926

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74314

African (AFR) AF: 0.000193 AC: 8 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2594A>G (p.E865G) alteration is located in exon 22 (coding exon 22) of the CFAP46 gene. This alteration results from a A to G substitution at nucleotide position 2594, causing the glutamic acid (E) at amino acid position 865 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.0
DANN	Benign	0.94
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.073
Sift	Benign	0.24	T
Sift4G	Benign	0.51	T
Vest4		0.17
MVP		0.040
MPC		0.13
ClinPred		0.20	T
GERP RS		-0.86
Varity_R		0.12
gMVP		0.070
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs753574836; hg19: chr10-134623919;