3-119709841-C-T

Position:

• chr3-119709841-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033364.4(CFAP91):​c.446C>T​(p.Pro149Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CFAP91 NM_033364.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP91	NM_033364.4	c.446C>T	p.Pro149Leu	missense_variant, splice_region_variant	5/18	ENST00000273390.9	NP_203528.3
CFAP91	NM_001320316.2	c.386C>T	p.Pro129Leu	missense_variant, splice_region_variant	5/18		NP_001307245.2
CFAP91	NM_001320317.2	c.260C>T	p.Pro87Leu	missense_variant, splice_region_variant	4/17		NP_001307246.2
CFAP91	NM_001320318.2	c.68C>T	p.Pro23Leu	missense_variant, splice_region_variant	3/16		NP_001307247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP91	ENST00000273390.9	c.446C>T	p.Pro149Leu	missense_variant, splice_region_variant	5/18	1	NM_033364.4	ENSP00000273390.5
ENSG00000285585	ENST00000648112.1	c.446C>T	p.Pro149Leu	missense_variant, splice_region_variant	5/18			ENSP00000497876.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Oct 20, 2023

The c.446C>T (p.P149L) alteration is located in exon 5 (coding exon 5) of the MAATS1 gene. This alteration results from a C to T substitution at nucleotide position 446, causing the proline (P) at amino acid position 149 to be replaced by a leucine (L). 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	0.26
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.063	T;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.15	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-7.0	D;D;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.84
MutPred		0.64		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.82
MPC		0.61
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.63
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs927479670; hg19: chr3-119428688;