3-119708661-A-G

Position:

• chr3-119708661-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033364.4(CFAP91):​c.430A>G​(p.Lys144Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000351 in 1,422,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CFAP91 NM_033364.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26

Genes affected

CFAP91 (HGNC:24010): (cilia and flagella associated protein 91) Predicted to be involved in cilium movement. Predicted to be located in axoneme and motile cilium. Predicted to colocalize with radial spoke stalk. Implicated in spermatogenic failure 51. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000285585 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP91	NM_033364.4	c.430A>G	p.Lys144Glu	missense_variant	4/18	ENST00000273390.9	NP_203528.3
CFAP91	NM_001320316.2	c.370A>G	p.Lys124Glu	missense_variant	4/18		NP_001307245.2
CFAP91	NM_001320317.2	c.244A>G	p.Lys82Glu	missense_variant	3/17		NP_001307246.2
CFAP91	NM_001320318.2	c.52A>G	p.Lys18Glu	missense_variant	2/16		NP_001307247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP91	ENST00000273390.9	c.430A>G	p.Lys144Glu	missense_variant	4/18	1	NM_033364.4	ENSP00000273390.5
ENSG00000285585	ENST00000648112.1	c.430A>G	p.Lys144Glu	missense_variant	4/18			ENSP00000497876.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000351 AC: 5 AN: 1422764 Hom.: 0 Cov.: 25 AF XY: 0.00000141 AC XY: 1 AN XY: 709436

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000370

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The c.430A>G (p.K144E) alteration is located in exon 4 (coding exon 4) of the MAATS1 gene. This alteration results from a A to G substitution at nucleotide position 430, causing the lysine (K) at amino acid position 144 to be replaced by a glutamic acid (E). 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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	26
DANN	Benign	0.81
DEOGEN2	Benign	0.13	T;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	.;T;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	0.011	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.1	D;D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.0050	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.80
MutPred		0.71		Loss of methylation at K144 (P = 0.0019);Loss of methylation at K144 (P = 0.0019);Loss of methylation at K144 (P = 0.0019);
MVP		0.74
MPC		0.70
ClinPred		0.89	D
GERP RS		6.0
Varity_R		0.68
gMVP		0.82

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: rs1397488258; hg19: chr3-119427508;