rs55643281

Positions:

• chr4-122934358-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_145207.3(SPATA5):​c.767T>C​(p.Ile256Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,614,192 control chromosomes in the GnomAD database, including 179 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I256V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0091 (9 hom., cov: 32)
  • Exomes 𝑓: 0.013 (170 hom.)
• Consequence: SPATA5 NM_145207.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.30

Genes affected

SPATA5 (HGNC:):

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=0.0034609437).
• BP6: Variant 4-122934358-T-C is Benign according to our data. Variant chr4-122934358-T-C is described in ClinVar as [Benign]. Clinvar id is 475734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-122934358-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0131 (19204/1461888) while in subpopulation NFE AF= 0.0153 (16984/1112006). AF 95% confidence interval is 0.0151. There are 170 homozygotes in gnomad4_exome. There are 9199 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPATA5	NM_145207.3	c.767T>C	p.Ile256Thr	missense_variant	5/16	ENST00000274008.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFG2A	ENST00000274008.5	c.767T>C	p.Ile256Thr	missense_variant	5/16	1	NM_145207.3	P1

Frequencies

GnomAD3 genomes AF: 0.00910 AC: 1385 AN: 152186 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00916 AC: 2302 AN: 251406 Hom.: 23 AF XY: 0.00914 AC XY: 1242 AN XY: 135870

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.00584

Gnomad ASJ exome AF: 0.0233

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0131 AC: 19204 AN: 1461888 Hom.: 170 Cov.: 31 AF XY: 0.0126 AC XY: 9199 AN XY: 727248

Gnomad4 AFR exome AF: 0.00284

Gnomad4 AMR exome AF: 0.00682

Gnomad4 ASJ exome AF: 0.0246

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.00489

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.00909 AC: 1385 AN: 152304 Hom.: 9 Cov.: 32 AF XY: 0.00845 AC XY: 629 AN XY: 74472

Gnomad4 AFR AF: 0.00359

Gnomad4 AMR AF: 0.00980

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0141 Hom.: 47

Bravo AF: 0.00920

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0159 AC: 137

ExAC AF: 0.00916 AC: 1112

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0143

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	AFG2A: BP4, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 16, 2020

- -

AFG2A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.37
DANN	Benign	0.41
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.040
MVP		0.34
MPC		0.18
ClinPred		0.0037	T
GERP RS		-5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.17

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: rs55643281; hg19: chr4-123855513; COSMIC: COSV99916787;