4-123256131-T-C

Position:

chr4-123256131-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_145207.3(SPATA5):c.2456T>C(p.Val819Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SPATA5
NM_145207.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 6.79

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-123256131-T-C is Pathogenic according to our data. Variant chr4-123256131-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548622.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPATA5	NM_145207.3 linkuse as main transcript	c.2456T>C	p.Val819Ala	missense_variant	15/16	ENST00000274008.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFG2A	ENST00000274008.5 linkuse as main transcript	c.2456T>C	p.Val819Ala	missense_variant	15/16	1	NM_145207.3	P1	Q8NB90-1
AFG2A	ENST00000675612.1 linkuse as main transcript	c.2525T>C	p.Val842Ala	missense_variant	16/17

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251228

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000192

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 27, 2021	This sequence change replaces valine with alanine at codon 819 of the SPATA5 protein (p.Val819Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs149604630, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with SPATA5-related conditions. ClinVar contains an entry for this variant (Variation ID: 548622). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31130284) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.21

Eigen

Benign

0.15

Eigen_PC

Benign

0.070

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

0.79

MutationTaster

Benign

0.96

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.60

Sift

Uncertain

0.026

Sift4G

Uncertain

0.0030

Polyphen

0.60

Vest4

0.54

MVP

0.89

MPC

0.37

ClinPred

0.88

GERP RS

3.7

Varity_R

0.22

gMVP

0.45

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