4-123162763-C-T

Variant names:

• chr4-123162763-C-T
• rs304650
• NM_145207.3:c.2340+72058C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_145207.3(AFG2A):​c.2340+72058C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 151,938 control chromosomes in the GnomAD database, including 26,900 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (26900 hom., cov: 31)
• Consequence: AFG2A NM_145207.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.287
• Publications: 8 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG2A	NM_145207.3	c.2340+72058C>T		intron_variant	Intron 14 of 15	ENST00000274008.5	NP_660208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG2A	ENST00000274008.5	c.2340+72058C>T		intron_variant	Intron 14 of 15	1	NM_145207.3	ENSP00000274008.3
AFG2A	ENST00000675612.1	c.2409+72058C>T		intron_variant	Intron 15 of 16			ENSP00000502453.1

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85284 AN: 151820 Hom.: 26895 Cov.: 31

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.838

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.562

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.562 AC: 85314 AN: 151938 Hom.: 26900 Cov.: 31 AF XY: 0.562 AC XY: 41786 AN XY: 74288

African (AFR) AF: 0.277 AC: 11460 AN: 41388

American (AMR) AF: 0.569 AC: 8696 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 1922 AN: 3466

East Asian (EAS) AF: 0.530 AC: 2731 AN: 5154

South Asian (SAS) AF: 0.386 AC: 1860 AN: 4824

European-Finnish (FIN) AF: 0.838 AC: 8862 AN: 10574

Middle Eastern (MID) AF: 0.408 AC: 119 AN: 292

European-Non Finnish (NFE) AF: 0.704 AC: 47857 AN: 67938

Other (OTH) AF: 0.564 AC: 1192 AN: 2114

Alfa AF: 0.641 Hom.: 100043

Bravo AF: 0.532

Asia WGS AF: 0.498 AC: 1729 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.3
DANN	Benign	0.48
PhyloP100		0.29
Mutation Taster		=100/0	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: rs304650; hg19: chr4-124083918;