4-123256160-G-T

Variant names:

• chr4-123256160-G-T
• rs35206443
• NM_145207.3:c.2485G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.28
• Publications: 10 publications found

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: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• syndromic complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

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, syndromic complex neurodevelopmental disorder.
• 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145207.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	NM_145207.3	MANE Select	c.2485G>T	p.Asp829Tyr	missense	Exon 15 of 16	NP_660208.2	Q8NB90-1
	AFG2A	NM_001438322.1		c.2557G>T	p.Asp853Tyr	missense	Exon 16 of 17	NP_001425251.1
	AFG2A	NM_001437913.1		c.2554G>T	p.Asp852Tyr	missense	Exon 16 of 17	NP_001424842.1	A0A6Q8PGU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	ENST00000274008.5	TSL:1 MANE Select	c.2485G>T	p.Asp829Tyr	missense	Exon 15 of 16	ENSP00000274008.3	Q8NB90-1
	AFG2A	ENST00000675612.1		c.2554G>T	p.Asp852Tyr	missense	Exon 16 of 17	ENSP00000502453.1	A0A6Q8PGU6
	AFG2A	ENST00000905945.1		c.2482G>T	p.Asp828Tyr	missense	Exon 15 of 16	ENSP00000576004.1

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

GnomAD2 exomes AF: 0.0118 AC: 2952 AN: 251172 AF XY: 0.0108

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.: 96 Cov.: 30 AF XY: 0.00767 AC XY: 5576 AN XY: 727180

African (AFR) AF: 0.00185 AC: 62 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

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

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: 25 AN: 3468

East Asian (EAS) AF: 0.00425 AC: 22 AN: 5182

South Asian (SAS) AF: 0.00831 AC: 40 AN: 4814

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10610

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00625 AC: 425 AN: 68016

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00700 Hom.: 24

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.3
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
Mutation Taster		=88/12	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35206443; hg19: chr4-124177315;