NM_001039706.3:c.546G>A

Variant names:

• chr7-90271539-G-A
• rs138300755
• NM_001039706.3:c.546G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001039706.3(CFAP69):​c.546G>A​(p.Ala182Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,611,198 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (15 hom.)
• Consequence: CFAP69 NM_001039706.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.714
• Publications: 1 publications found

Genes affected

CFAP69 (HGNC:26107): (cilia and flagella associated protein 69) Acts upstream of or within sperm axoneme assembly. Located in cytoplasm and sperm midpiece. Implicated in spermatogenic failure 24. [provided by Alliance of Genome Resources, Apr 2022]

CFAP69 Gene-Disease associations (from GenCC):

• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 24

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 7-90271539-G-A is Benign according to our data. Variant chr7-90271539-G-A is described in ClinVar as Benign. ClinVar VariationId is 709810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.714 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00671 (1021/152120) while in subpopulation AFR AF = 0.022 (912/41494). AF 95% confidence interval is 0.0208. There are 11 homozygotes in GnomAd4. There are 474 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039706.3. 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
	CFAP69	NM_001039706.3	MANE Select	c.546G>A	p.Ala182Ala	synonymous	Exon 7 of 23	NP_001034795.2	A5D8W1-1
	CFAP69	NM_001160138.2		c.492G>A	p.Ala164Ala	synonymous	Exon 7 of 23	NP_001153610.1	A5D8W1-5
	CFAP69	NM_001363438.1		c.546G>A	p.Ala182Ala	synonymous	Exon 7 of 22	NP_001350367.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP69	ENST00000389297.8	TSL:1 MANE Select	c.546G>A	p.Ala182Ala	synonymous	Exon 7 of 23	ENSP00000373948.4	A5D8W1-1
	CFAP69	ENST00000497910.5	TSL:2	c.492G>A	p.Ala164Ala	synonymous	Exon 7 of 23	ENSP00000419549.1	A5D8W1-5
	CFAP69	ENST00000949775.1		c.447G>A	p.Ala149Ala	synonymous	Exon 6 of 22	ENSP00000619834.1

Frequencies

GnomAD3 genomes AF: 0.00671 AC: 1020 AN: 152002 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00817

GnomAD2 exomes AF: 0.00196 AC: 487 AN: 248420 AF XY: 0.00150

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000506

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.000942 AC: 1374 AN: 1459078 Hom.: 15 Cov.: 31 AF XY: 0.000882 AC XY: 640 AN XY: 725742

African (AFR) AF: 0.0198 AC: 660 AN: 33396

American (AMR) AF: 0.00341 AC: 152 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85836

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.00535 AC: 25 AN: 4672

European-Non Finnish (NFE) AF: 0.000347 AC: 386 AN: 1111242

Other (OTH) AF: 0.00248 AC: 149 AN: 60194

GnomAD4 genome AF: 0.00671 AC: 1021 AN: 152120 Hom.: 11 Cov.: 33 AF XY: 0.00637 AC XY: 474 AN XY: 74388

African (AFR) AF: 0.0220 AC: 912 AN: 41494

American (AMR) AF: 0.00380 AC: 58 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 67980

Other (OTH) AF: 0.00809 AC: 17 AN: 2102

Alfa AF: 0.00310 Hom.: 4

Bravo AF: 0.00769

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000602

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CFAP69-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.2
DANN	Benign	0.57
PhyloP100		-0.71
PromoterAI		0.015	Neutral
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: rs138300755; hg19: chr7-89900853;