4-123256160-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_145207.3(AFG2A):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. 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

AFG2A
NM_145207.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.28

Publications

10 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.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.46019 (below the threshold of 3.09). Trascript score misZ: 1.2041 (below the threshold of 3.09). GenCC associations: The gene is linked to microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG2A	NM_145207.3 link	c.2485G>T	p.Asp829Tyr	missense_variant	Exon 15 of 16	ENST00000274008.5	NP_660208.2	Q8NB90-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG2A	ENST00000274008.5 link	c.2485G>T	p.Asp829Tyr	missense_variant	Exon 15 of 16	1	NM_145207.3	ENSP00000274008.3		Q8NB90-1
AFG2A	ENST00000675612.1 link	c.2554G>T	p.Asp852Tyr	missense_variant	Exon 16 of 17			ENSP00000502453.1		A0A6Q8PGU6

Frequencies

GnomAD3 genomes

AF:

0.00632

AC:

962

AN:

152114

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0118

AC:

2952

AN:

251172

AF XY:

0.0108

show subpopulations

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 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.:

Cov.:

AF XY:

0.00767

AC XY:

5576

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

33480

American (AMR)

AF:

0.0420

AC:

1877

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00842

AC:

220

AN:

26134

East Asian (EAS)

AF:

0.00252

AC:

100

AN:

39696

South Asian (SAS)

AF:

0.00913

AC:

787

AN:

86228

European-Finnish (FIN)

AF:

0.00286

AC:

153

AN:

53416

Middle Eastern (MID)

AF:

0.0198

AC:

114

AN:

5768

European-Non Finnish (NFE)

AF:

0.00688

AC:

7650

AN:

1111944

Other (OTH)

AF:

0.00798

AC:

482

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

590

1180

1770

2360

2950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

330

660

990

1320

1650

<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:

0.00633

AC:

964

AN:

152232

Hom.:

Cov.:

AF XY:

0.00611

AC XY:

455

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00243

AC:

101

AN:

41528

American (AMR)

AF:

0.0186

AC:

284

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00721

AC:

AN:

3468

East Asian (EAS)

AF:

0.00425

AC:

AN:

5182

South Asian (SAS)

AF:

0.00831

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00625

AC:

425

AN:

68016

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

103

155

206

258

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:

0.00700

Hom.:

Bravo

AF:

0.00859

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.0102

AC:

1239

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00780

EpiControl

AF:

0.00765

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 29, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 26, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Oct 03, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.23

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0062

MetaSVM

Uncertain

0.24

PhyloP100

1.3

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.49

Vest4

0.67

MPC

0.35

ClinPred

0.057

GERP RS

3.1

Varity_R

0.72

gMVP

0.57

Mutation Taster

=88/12

polymorphism (auto)

(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