4-122979302-G-T

Variant names:

• chr4-122979302-G-T
• rs62324113
• NM_145207.3:c.1785G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.64
• Publications: 3 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.

• 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

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.1785G>T	p.Val595Val	synonymous	Exon 10 of 16	NP_660208.2	Q8NB90-1
	AFG2A	NM_001438322.1		c.1857G>T	p.Val619Val	synonymous	Exon 11 of 17	NP_001425251.1
	AFG2A	NM_001437913.1		c.1854G>T	p.Val618Val	synonymous	Exon 11 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.1785G>T	p.Val595Val	synonymous	Exon 10 of 16	ENSP00000274008.3	Q8NB90-1
	AFG2A	ENST00000422835.2	TSL:1	n.1827G>T		non_coding_transcript_exon	Exon 10 of 15
	AFG2A	ENST00000675612.1		c.1854G>T	p.Val618Val	synonymous	Exon 11 of 17	ENSP00000502453.1	A0A6Q8PGU6

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

GnomAD2 exomes AF: 0.0115 AC: 2891 AN: 251472 AF XY: 0.0131

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.: 30 AF XY: 0.0123 AC XY: 8932 AN XY: 727230

African (AFR) AF: 0.00170 AC: 57 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: 2 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: 76 AN: 5768

European-Non Finnish (NFE) AF: 0.0112 AC: 12481 AN: 1112000

Other (OTH) AF: 0.0121 AC: 730 AN: 60394

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

African (AFR) AF: 0.00197 AC: 82 AN: 41582

American (AMR) AF: 0.0178 AC: 272 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 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: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 731 AN: 68028

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00844 Hom.: 5

Bravo AF: 0.00768

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.0119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (2)
-	-	2	not provided (2)
-	-	1	AFG2A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.5
DANN	Benign	0.66
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism

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: rs62324113; hg19: chr4-123900457; COSMIC: COSV107270642;