NM_001131066.2:c.365T>C

Variant names:

• chr5-95654363-T-C
• rs200861427
• NM_001131066.2:c.365T>C

Variant summary

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

The NM_001131066.2(RFESD):​c.365T>C​(p.Ile122Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,588,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: RFESD NM_001131066.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.05
• Publications: 0 publications found

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001131066.2. 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
	RFESD	NM_001131066.2	MANE Select	c.365T>C	p.Ile122Thr	missense	Exon 5 of 6	NP_001124538.1	Q8TAC1-2
	RFESD	NM_001131065.1		c.365T>C	p.Ile122Thr	missense	Exon 5 of 6	NP_001124537.1	Q8TAC1-2
	RFESD	NM_001375394.1		c.206T>C	p.Ile69Thr	missense	Exon 4 of 5	NP_001362323.1	Q8TAC1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFESD	ENST00000380005.9	TSL:2 MANE Select	c.365T>C	p.Ile122Thr	missense	Exon 5 of 6	ENSP00000369341.4	Q8TAC1-2
	RFESD	ENST00000311364.9	TSL:1	c.206T>C	p.Ile69Thr	missense	Exon 4 of 5	ENSP00000309229.4	Q8TAC1-1
	SPATA9	ENST00000316087.12	TSL:1	n.*447+968A>G		intron	N/A	ENSP00000325491.8	Q9BWV2-1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

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: 0.0000244 AC: 6 AN: 245776 AF XY: 0.0000150

Gnomad AFR exome AF: 0.000388

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000557 AC: 8 AN: 1436584 Hom.: 0 Cov.: 28 AF XY: 0.00000419 AC XY: 3 AN XY: 715538

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000123 AC: 4 AN: 32604

American (AMR) AF: 0.00 AC: 0 AN: 43112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25734

East Asian (EAS) AF: 0.00 AC: 0 AN: 39458

South Asian (SAS) AF: 0.00 AC: 0 AN: 83652

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4250

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1095264

Other (OTH) AF: 0.00 AC: 0 AN: 59312

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00124846), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74358

African (AFR) AF: 0.000386 AC: 16 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000946 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000495 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.29
MPC		0.68
ClinPred		0.88	D
GERP RS		5.7
PromoterAI		0.0081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.90
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200861427; hg19: chr5-94990067;