4-123256160-G-T

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.2485G>T(p.Asp829Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00769 in 1,614,010 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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. D829N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0063 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (96 hom.)
• Consequence: SPATA5 NM_145207.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.28

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=0.0061918497).
• BP6: Variant 4-123256160-G-T is Benign according to our data. Variant chr4-123256160-G-T is described in ClinVar as [Benign]. Clinvar id is 436841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00633 (964/152232) while in subpopulation AMR AF= 0.0186 (284/15294). AF 95% confidence interval is 0.0168. There are 4 homozygotes in gnomad4. There are 455 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPATA5	NM_145207.3	c.2485G>T	p.Asp829Tyr	missense_variant	15/16	ENST00000274008.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFG2A	ENST00000274008.5	c.2485G>T	p.Asp829Tyr	missense_variant	15/16	1	NM_145207.3	P1
AFG2A	ENST00000675612.1	c.2554G>T	p.Asp852Tyr	missense_variant	16/17

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 962 AN: 152114 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.00809

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00625

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0118 AC: 2952 AN: 251172 Hom.: 46 AF XY: 0.0108 AC XY: 1461 AN XY: 135732

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.0450

Gnomad ASJ exome AF: 0.00685

Gnomad EAS exome AF: 0.00337

Gnomad SAS exome AF: 0.00951

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00715

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00783 AC: 11445 AN: 1461778 Hom.: 96 Cov.: 30 AF XY: 0.00767 AC XY: 5576 AN XY: 727180

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.0420

Gnomad4 ASJ exome AF: 0.00842

Gnomad4 EAS exome AF: 0.00252

Gnomad4 SAS exome AF: 0.00913

Gnomad4 FIN exome AF: 0.00286

Gnomad4 NFE exome AF: 0.00688

Gnomad4 OTH exome AF: 0.00798

GnomAD4 genome AF: 0.00633 AC: 964 AN: 152232 Hom.: 4 Cov.: 32 AF XY: 0.00611 AC XY: 455 AN XY: 74442

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00425

Gnomad4 SAS AF: 0.00831

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00625

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00684 Hom.: 16

Bravo AF: 0.00859

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.0102 AC: 1239

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.00780

EpiControl AF: 0.00765

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 03, 2019

- -

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	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	20
Dann	Benign	0.82
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0062	T
MetaSVM	Uncertain	0.24	D
MutationTaster	Benign	0.78	N
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.49	P
Vest4		0.67
MPC		0.35
ClinPred		0.057	T
GERP RS		3.1
Varity_R		0.72
gMVP		0.57

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: rs35206443; hg19: chr4-124177315;