5-95654227-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001131066.2(RFESD):c.325C>A(p.Arg109Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R109C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFESD NM_001131066.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91

Genes affected

RFESD (HGNC:29587): (Rieske Fe-S domain containing) Predicted to enable 2 iron, 2 sulfur cluster binding activity and metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

SPATA9 (HGNC:22988): (spermatogenesis associated 9) Predicted to be involved in cell differentiation and spermatogenesis. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFESD	NM_001131066.2	c.325C>A	p.Arg109Ser	missense_variant	4/6	ENST00000380005.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFESD	ENST00000380005.9	c.325C>A	p.Arg109Ser	missense_variant	4/6	2	NM_001131066.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Oct 26, 2021

The c.325C>A (p.R109S) alteration is located in exon 4 (coding exon 3) of the RFESD gene. This alteration results from a C to A substitution at nucleotide position 325, causing the arginine (R) at amino acid position 109 to be replaced by a serine (S). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.032	T;.;T;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;.;D;D;D
M_CAP	Benign	0.0046	T
MetaRNN	Uncertain	0.65	D;D;D;D;D
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	N;N;N;N;D
REVEL	Benign	0.28
Sift	Benign	0.36	T;T;T;T;D
Sift4G	Benign	0.36	T;T;T;T;D
Polyphen		1.0	D;.;D;.;D
Vest4		0.68, 0.70, 0.67, 0.69
MutPred		0.58		Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);
MVP		0.23
MPC		0.59
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-94989931;