4-122934358-T-C

Position:

chr4-122934358-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.30

Variant links:

Genes affected

SPATA5 (HGNC:):

SPATA5 links:

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]

AFG2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.767T>C	p.Ile256Thr	missense_variant	5/16	1	NM_145207.3	P1	Q8NB90-1

Frequencies

GnomAD3 genomes

AF:

0.00910

AC:

1385

AN:

152186

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00914

AC XY:

1242

AN XY:

135870

show subpopulations

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.:

AF XY:

0.0126

AC XY:

9199

AN XY:

727248

show subpopulations

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.:

Cov.:

AF XY:

0.00845

AC XY:

629

AN XY:

74472

show subpopulations

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.:

Bravo

AF:

0.00920

TwinsUK

AF:

0.0170

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0159

AC:

137

ExAC

AF:

0.00916

AC:

1112

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0143

EpiControl

AF:

0.0143

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.37

DANN

Benign

0.41

DEOGEN2

Benign

0.010

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0035

MetaSVM

Benign

-0.66

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.58

REVEL

Benign

0.16

Sift

Benign

1.0

Sift4G

Benign

0.44

Polyphen

0.0

Vest4

0.040

MVP

0.34

MPC

0.18

ClinPred

0.0037

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over