rs1472949

Variant names:

• chr4-123028401-G-A
• rs1472949
• NM_145207.3:c.2079+6G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-123028401-G-A
• chr4-123028401-G-C
• chr4-123028401-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145207.3(AFG2A):​c.2079+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.939 in 1,613,580 control chromosomes in the GnomAD database, including 712,732 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61328 hom., cov: 32)
  • Exomes 𝑓: 0.94 (651404 hom.)
• Consequence: AFG2A NM_145207.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001721
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.739
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-123028401-G-A is Benign according to our data. Variant chr4-123028401-G-A is described in ClinVar as Benign. ClinVar VariationId is 203522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.945 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.2079+6G>A		splice_region intron	N/A	NP_660208.2	Q8NB90-1
	AFG2A	NM_001317799.2		c.2082G>A	p.Gly694Gly	synonymous	Exon 11 of 11	NP_001304728.1
	AFG2A	NM_001438322.1		c.2151+6G>A		splice_region intron	N/A	NP_001425251.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	ENST00000274008.5	TSL:1 MANE Select	c.2079+6G>A		splice_region intron	N/A	ENSP00000274008.3	Q8NB90-1
	AFG2A	ENST00000422835.2	TSL:1	n.2121+6G>A		splice_region intron	N/A
	AFG2A	ENST00000675612.1		c.2148+6G>A		splice_region intron	N/A	ENSP00000502453.1	A0A6Q8PGU6

Frequencies

GnomAD3 genomes AF: 0.895 AC: 136065 AN: 152092 Hom.: 61286 Cov.: 32

Gnomad AFR AF: 0.788

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 0.959

Gnomad SAS AF: 0.912

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.951

Gnomad OTH AF: 0.887

GnomAD2 exomes AF: 0.917 AC: 230262 AN: 251028 AF XY: 0.922

Gnomad AFR exome AF: 0.790

Gnomad AMR exome AF: 0.850

Gnomad ASJ exome AF: 0.918

Gnomad EAS exome AF: 0.963

Gnomad FIN exome AF: 0.927

Gnomad NFE exome AF: 0.948

Gnomad OTH exome AF: 0.915

GnomAD4 exome AF: 0.943 AC: 1378684 AN: 1461370 Hom.: 651404 Cov.: 38 AF XY: 0.943 AC XY: 685306 AN XY: 727022

African (AFR) AF: 0.783 AC: 26200 AN: 33458

American (AMR) AF: 0.851 AC: 38065 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.916 AC: 23921 AN: 26128

East Asian (EAS) AF: 0.958 AC: 38024 AN: 39684

South Asian (SAS) AF: 0.911 AC: 78576 AN: 86244

European-Finnish (FIN) AF: 0.930 AC: 49689 AN: 53414

Middle Eastern (MID) AF: 0.824 AC: 4743 AN: 5758

European-Non Finnish (NFE) AF: 0.956 AC: 1063089 AN: 1111588

Other (OTH) AF: 0.934 AC: 56377 AN: 60372

GnomAD4 genome AF: 0.895 AC: 136167 AN: 152210 Hom.: 61328 Cov.: 32 AF XY: 0.894 AC XY: 66535 AN XY: 74410

African (AFR) AF: 0.788 AC: 32706 AN: 41512

American (AMR) AF: 0.871 AC: 13318 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.920 AC: 3195 AN: 3472

East Asian (EAS) AF: 0.959 AC: 4975 AN: 5186

South Asian (SAS) AF: 0.912 AC: 4400 AN: 4824

European-Finnish (FIN) AF: 0.929 AC: 9839 AN: 10596

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.951 AC: 64714 AN: 68022

Other (OTH) AF: 0.889 AC: 1872 AN: 2106

Alfa AF: 0.932 Hom.: 275772

Bravo AF: 0.884

Asia WGS AF: 0.937 AC: 3259 AN: 3478

EpiCase AF: 0.950

EpiControl AF: 0.943

ClinVar

ClinVar submissions

Significance: 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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.54
PhyloP100		-0.74
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.010
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: rs1472949; hg19: chr4-123949556;