rs376606287

Variant names:

• chr4-122936090-T-C
• rs376606287
• NM_145207.3:c.1278-10T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_145207.3(AFG2A):​c.1278-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,593,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: AFG2A NM_145207.3 intron
• Scores: Splicing: ADA: 0.0001980
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.90
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-122936090-T-C is Benign according to our data. Variant chr4-122936090-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542394.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000187 (270/1441032) while in subpopulation SAS AF = 0.00146 (119/81594). AF 95% confidence interval is 0.00125. There are 0 homozygotes in GnomAdExome4. There are 153 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	NM_145207.3	MANE Select	c.1278-10T>C		intron	N/A	NP_660208.2
	AFG2A	NM_001438322.1		c.1278-10T>C		intron	N/A	NP_001425251.1
	AFG2A	NM_001437913.1		c.1275-10T>C		intron	N/A	NP_001424842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	ENST00000274008.5	TSL:1 MANE Select	c.1278-10T>C		intron	N/A	ENSP00000274008.3
	AFG2A	ENST00000422835.2	TSL:1	n.1320-10T>C		intron	N/A
	AFG2A	ENST00000675612.1		c.1275-10T>C		intron	N/A	ENSP00000502453.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000253 AC: 61 AN: 240696 AF XY: 0.000308

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000187 AC: 270 AN: 1441032 Hom.: 0 Cov.: 29 AF XY: 0.000214 AC XY: 153 AN XY: 715850

African (AFR) AF: 0.0000608 AC: 2 AN: 32908

American (AMR) AF: 0.00 AC: 0 AN: 41862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25658

East Asian (EAS) AF: 0.00 AC: 0 AN: 39166

South Asian (SAS) AF: 0.00146 AC: 119 AN: 81594

European-Finnish (FIN) AF: 0.0000756 AC: 4 AN: 52918

Middle Eastern (MID) AF: 0.000707 AC: 4 AN: 5658

European-Non Finnish (NFE) AF: 0.000119 AC: 131 AN: 1101796

Other (OTH) AF: 0.000168 AC: 10 AN: 59472

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74502

African (AFR) AF: 0.0000481 AC: 2 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000147

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	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
BayesDel_noAF	Benign	-0.83
CADD	Benign	15
DANN	Benign	0.56
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.020		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: rs376606287; hg19: chr4-123857245; COSMIC: COSV56787746;