4-123028234-G-C

Position:

• chr4-123028234-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145207.3(AFG2A):​c.1918G>C​(p.Glu640Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0272 in 1,614,012 control chromosomes in the GnomAD database, including 1,561 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (164 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1397 hom.)
• Consequence: AFG2A NM_145207.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.73

Genes affected

AFG2A (HGNC:18119): (AFG2 AAA ATPase homolog A) This gene encodes a member of the ATPase associated with diverse activities family, whose members are defined by a highly conserved ATPase domain. Members of this family participate in diverse cellular processes that include membrane fusion, DNA replication, microtubule severing, and protein degradation. The protein encoded by this gene has a putative mitochondrial targeting sequence and has been proposed to function in maintenance of mitochondrial function and integrity during mouse spermatogenesis. Allelic variants in this gene have been associated with epilepsy, hearing loss, and cognitive disability syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

SPATA5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013232529).
• BP6: Variant 4-123028234-G-C is Benign according to our data. Variant chr4-123028234-G-C is described in ClinVar as [Benign]. Clinvar id is 475724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFG2A	NM_145207.3	c.1918G>C	p.Glu640Gln	missense_variant	11/16	ENST00000274008.5	NP_660208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPATA5	ENST00000274008.5	c.1918G>C	p.Glu640Gln	missense_variant	11/16	1	NM_145207.3	ENSP00000274008.3
SPATA5	ENST00000422835.2	n.1960G>C		non_coding_transcript_exon_variant	11/15	1
SPATA5	ENST00000675612.1	c.1987G>C	p.Glu663Gln	missense_variant	12/17			ENSP00000502453.1

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5075 AN: 152084 Hom.: 165 Cov.: 32

Gnomad AFR AF: 0.0574

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.00924

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0410 AC: 10319 AN: 251442 Hom.: 502 AF XY: 0.0452 AC XY: 6144 AN XY: 135892

Gnomad AFR exome AF: 0.0599

Gnomad AMR exome AF: 0.0575

Gnomad ASJ exome AF: 0.0329

Gnomad EAS exome AF: 0.00843

Gnomad SAS exome AF: 0.146

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0327

GnomAD4 exome AF: 0.0266 AC: 38816 AN: 1461810 Hom.: 1397 Cov.: 32 AF XY: 0.0299 AC XY: 21746 AN XY: 727206

Gnomad4 AFR exome AF: 0.0567

Gnomad4 AMR exome AF: 0.0552

Gnomad4 ASJ exome AF: 0.0343

Gnomad4 EAS exome AF: 0.00877

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.00387

Gnomad4 NFE exome AF: 0.0166

Gnomad4 OTH exome AF: 0.0321

GnomAD4 genome AF: 0.0334 AC: 5084 AN: 152202 Hom.: 164 Cov.: 32 AF XY: 0.0343 AC XY: 2552 AN XY: 74424

Gnomad4 AFR AF: 0.0575

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.0404

Gnomad4 EAS AF: 0.00926

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.0326

Alfa AF: 0.0161 Hom.: 11

Bravo AF: 0.0348

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.0597 AC: 263

ESP6500EA AF: 0.0173 AC: 149

ExAC AF: 0.0424 AC: 5151

Asia WGS AF: 0.0990 AC: 344 AN: 3478

EpiCase AF: 0.0249

EpiControl AF: 0.0232

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2018

- -

Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.78	T
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.26
Sift	Benign	0.35	T
Sift4G	Benign	0.24	T
Polyphen		0.0010	B
Vest4		0.13
MPC		0.14
ClinPred		0.0074	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.66

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: rs35343500; hg19: chr4-123949389;