4-122979302-G-T

Position:

• chr4-122979302-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_145207.3(SPATA5):​c.1785G>T​(p.Val595=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,614,198 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (12 hom., cov: 33)
  • Exomes 𝑓: 0.012 (146 hom.)
• Consequence: SPATA5 NM_145207.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.64

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 4-122979302-G-T is Benign according to our data. Variant chr4-122979302-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 475723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.64 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00912 (1390/152330) while in subpopulation SAS AF= 0.028 (135/4824). AF 95% confidence interval is 0.0241. There are 12 homozygotes in gnomad4. There are 770 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPATA5	NM_145207.3	c.1785G>T	p.Val595=	synonymous_variant	10/16	ENST00000274008.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFG2A	ENST00000274008.5	c.1785G>T	p.Val595=	synonymous_variant	10/16	1	NM_145207.3	P1
AFG2A	ENST00000422835.2	n.1827G>T		non_coding_transcript_exon_variant	10/15	1
AFG2A	ENST00000675612.1	c.1854G>T	p.Val618=	synonymous_variant	11/17
AFG2A	ENST00000674886.1	n.1847G>T		non_coding_transcript_exon_variant	10/11

Frequencies

GnomAD3 genomes AF: 0.00913 AC: 1389 AN: 152212 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.0115 AC: 2891 AN: 251472 Hom.: 26 AF XY: 0.0131 AC XY: 1785 AN XY: 135904

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00916

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0284

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0117 AC: 17062 AN: 1461868 Hom.: 146 Cov.: 30 AF XY: 0.0123 AC XY: 8932 AN XY: 727230

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0107

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0286

Gnomad4 FIN exome AF: 0.00951

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00912 AC: 1390 AN: 152330 Hom.: 12 Cov.: 33 AF XY: 0.0103 AC XY: 770 AN XY: 74494

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.0178

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0280

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00996 Hom.: 5

Bravo AF: 0.00768

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.0119

ClinVar

Significance: Benign/Likely 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	Athena Diagnostics	Feb 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2021	- -

Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2022	- -

AFG2A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.5
DANN	Benign	0.66

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: rs62324113; hg19: chr4-123900457;