rs35343500

Variant names:

• chr4-123028234-G-C
• rs35343500
• NM_145207.3:c.1918G>C

Your query was ambiguous. Multiple possible variants found:

• chr4-123028234-G-C
• chr4-123028234-G-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_145207.3(AFG2A):​c.1918G>C​(p.Glu640Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0272 in 1,614,012 control chromosomes in the GnomAD database, including 1,561 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (164 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1397 hom.)
• Consequence: AFG2A NM_145207.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.73
• Publications: 7 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=0.0013232529).
• BP6: Variant 4-123028234-G-C is Benign according to our data. Variant chr4-123028234-G-C is described in ClinVar as Benign. ClinVar VariationId is 475724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

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.1918G>C	p.Glu640Gln	missense	Exon 11 of 16	NP_660208.2	Q8NB90-1
	AFG2A	NM_001438322.1		c.1990G>C	p.Glu664Gln	missense	Exon 12 of 17	NP_001425251.1
	AFG2A	NM_001437913.1		c.1987G>C	p.Glu663Gln	missense	Exon 12 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.1918G>C	p.Glu640Gln	missense	Exon 11 of 16	ENSP00000274008.3	Q8NB90-1
	AFG2A	ENST00000422835.2	TSL:1	n.1960G>C		non_coding_transcript_exon	Exon 11 of 15
	AFG2A	ENST00000675612.1		c.1987G>C	p.Glu663Gln	missense	Exon 12 of 17	ENSP00000502453.1	A0A6Q8PGU6

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5075 AN: 152084 Hom.: 165 Cov.: 32

Gnomad AFR AF: 0.0574

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.00924

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0410 AC: 10319 AN: 251442 AF XY: 0.0452

Gnomad AFR exome AF: 0.0599

Gnomad AMR exome AF: 0.0575

Gnomad ASJ exome AF: 0.0329

Gnomad EAS exome AF: 0.00843

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0327

GnomAD4 exome AF: 0.0266 AC: 38816 AN: 1461810 Hom.: 1397 Cov.: 32 AF XY: 0.0299 AC XY: 21746 AN XY: 727206

African (AFR) AF: 0.0567 AC: 1897 AN: 33478

American (AMR) AF: 0.0552 AC: 2470 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 897 AN: 26124

East Asian (EAS) AF: 0.00877 AC: 348 AN: 39690

South Asian (SAS) AF: 0.143 AC: 12300 AN: 86250

European-Finnish (FIN) AF: 0.00387 AC: 207 AN: 53420

Middle Eastern (MID) AF: 0.0589 AC: 340 AN: 5768

European-Non Finnish (NFE) AF: 0.0166 AC: 18421 AN: 1111964

Other (OTH) AF: 0.0321 AC: 1936 AN: 60392

GnomAD4 genome AF: 0.0334 AC: 5084 AN: 152202 Hom.: 164 Cov.: 32 AF XY: 0.0343 AC XY: 2552 AN XY: 74424

African (AFR) AF: 0.0575 AC: 2387 AN: 41510

American (AMR) AF: 0.0325 AC: 497 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 140 AN: 3468

East Asian (EAS) AF: 0.00926 AC: 48 AN: 5182

South Asian (SAS) AF: 0.146 AC: 703 AN: 4822

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10604

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1167 AN: 68006

Other (OTH) AF: 0.0326 AC: 69 AN: 2116

Alfa AF: 0.0161 Hom.: 11

Bravo AF: 0.0348

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.0597 AC: 263

ESP6500EA AF: 0.0173 AC: 149

ExAC AF: 0.0424 AC: 5151

Asia WGS AF: 0.0990 AC: 344 AN: 3478

EpiCase AF: 0.0249

EpiControl AF: 0.0232

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.78	T
PhyloP100		3.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.26
Sift	Benign	0.35	T
Sift4G	Benign	0.24	T
Polyphen		0.0010	B
Vest4		0.13
MPC		0.14
ClinPred		0.0074	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.66
Mutation Taster		=99/1	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: rs35343500; hg19: chr4-123949389;