4-122923222-G-C

Position:

• chr4-122923222-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.80G>C​(p.Cys27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00849 in 1,614,156 control chromosomes in the GnomAD database, including 906 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (458 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (448 hom.)
• Consequence: AFG2A NM_145207.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.322

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015427172).
• BP6: Variant 4-122923222-G-C is Benign according to our data. Variant chr4-122923222-G-C is described in ClinVar as [Benign]. Clinvar id is 475736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFG2A	NM_145207.3	c.80G>C	p.Cys27Ser	missense_variant	1/16	ENST00000274008.5	NP_660208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPATA5	ENST00000274008.5	c.80G>C	p.Cys27Ser	missense_variant	1/16	1	NM_145207.3	ENSP00000274008.3
SPATA5	ENST00000422835.2	n.122G>C		non_coding_transcript_exon_variant	1/15	1
SPATA5	ENST00000675612.1	c.80G>C	p.Cys27Ser	missense_variant	1/17			ENSP00000502453.1
SPATA5	ENST00000674886.1	n.145G>C		non_coding_transcript_exon_variant	1/11

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6526 AN: 152162 Hom.: 461 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0119 AC: 2998 AN: 251454 Hom.: 200 AF XY: 0.00850 AC XY: 1155 AN XY: 135906

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.00922

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000791

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00491 AC: 7174 AN: 1461874 Hom.: 448 Cov.: 31 AF XY: 0.00421 AC XY: 3063 AN XY: 727236

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000450

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.0429 AC: 6535 AN: 152282 Hom.: 458 Cov.: 32 AF XY: 0.0410 AC XY: 3051 AN XY: 74478

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.0173

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.0326

Alfa AF: 0.00475 Hom.: 6

Bravo AF: 0.0479

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.141 AC: 620

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.0138 AC: 1675

Asia WGS AF: 0.00751 AC: 27 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 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 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.5
DANN	Benign	0.65
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.66	N
REVEL	Benign	0.12
Sift	Benign	0.58	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.039
MutPred		0.26		Gain of loop (P = 0.0166);
MPC		0.18
ClinPred		0.0037	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072
gMVP		0.12

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: rs35430470; hg19: chr4-123844377;