NM_145207.3:c.1785G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_145207.3(AFG2A):c.1785G>T(p.Val595Val) 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

AFG2A
NM_145207.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.64

Publications

3 publications found

Variant links:

Genes affected

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 Gene-Disease associations (from GenCC):

microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, PanelApp Australia

AFG2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG2A	NM_145207.3 link	c.1785G>T	p.Val595Val	synonymous_variant	Exon 10 of 16	ENST00000274008.5	NP_660208.2	Q8NB90-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AFG2A	ENST00000274008.5 link	c.1785G>T	p.Val595Val	synonymous_variant	Exon 10 of 16	1	NM_145207.3	ENSP00000274008.3	Q8NB90-1
AFG2A	ENST00000422835.2 link	n.1827G>T		non_coding_transcript_exon_variant	Exon 10 of 15	1
AFG2A	ENST00000675612.1 link	c.1854G>T	p.Val618Val	synonymous_variant	Exon 11 of 17			ENSP00000502453.1	A0A6Q8PGU6
AFG2A	ENST00000674886.1 link	n.1847G>T		non_coding_transcript_exon_variant	Exon 10 of 11

Frequencies

GnomAD3 genomes

AF:

0.00913

AC:

1389

AN:

152212

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0115

AC:

2891

AN:

251472

AF XY:

0.0131

show subpopulations

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 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.:

AF XY:

0.0123

AC XY:

8932

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00170

AC:

AN:

33480

American (AMR)

AF:

0.0102

AC:

457

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

280

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0286

AC:

2471

AN:

86248

European-Finnish (FIN)

AF:

0.00951

AC:

508

AN:

53418

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0112

AC:

12481

AN:

1112000

Other (OTH)

AF:

0.0121

AC:

730

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

871

1742

2613

3484

4355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

476

952

1428

1904

2380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00912

AC:

1390

AN:

152330

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

770

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

41582

American (AMR)

AF:

0.0178

AC:

272

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0280

AC:

135

AN:

4824

European-Finnish (FIN)

AF:

0.0106

AC:

113

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0107

AC:

731

AN:

68028

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

140

209

279

349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00844

Hom.:

Bravo

AF:

0.00768

Asia WGS

AF:

0.00837

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 09, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 17, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AFG2A-related disorder

Benign:1

Aug 07, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

DANN

Benign

0.66

PhyloP100

2.6

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over