NM_145207.3:c.2219_2220delTAinsCT

Variant names:

• chr4-123090584-TA-CT
• NM_145207.3:c.2219_2220delTAinsCT
• AFG2A p.Leu740Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_145207.3(AFG2A):c.2219_2220delTAinsCT (p.Leu740Ser) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.L740S: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 475725)

• Frequency: Genomes: not found (cov: 33)
• Consequence: AFG2A NM_145207.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.61
• Publications: 0 publications found

Genes affected

AFG2A (HGNC:18119): (AAA ATPase AFG2A) 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), Orphanet, G2P, PanelApp Australia
• syndromic complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_145207.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AFG2A NM_145207.3	MANE Select	c.2219_2220delTAinsCT p.Leu740Ser	missense	N/A	Prot: NP_660208.2 UniProt:
	AFG2A NM_001438322.1		c.2291_2292delTAinsCT p.Leu764Ser	missense	N/A	Prot: NP_001425251.1
	AFG2A NM_001437913.1		c.2288_2289delTAinsCT p.Leu763Ser	missense	N/A	Prot: NP_001424842.1 UniProt:

AFG2A NM_145207.3

MANE Select

HGVSc / HGVSpc.2219_2220delTAinsCTp.Leu740Ser

Exon rankN/A

missense

Prot: NP_660208.2UniProt: Q8NB90-1

AFG2A NM_001438322.1

HGVSc / HGVSpc.2291_2292delTAinsCTp.Leu764Ser

Exon rankN/A

missense

Prot: NP_001425251.1

AFG2A NM_001437913.1

HGVSc / HGVSpc.2288_2289delTAinsCTp.Leu763Ser

Exon rankN/A

missense

Prot: NP_001424842.1UniProt: A0A6Q8PGU6

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AFG2A ENST00000274008.5	TSL:1MANE Select	c.2219_2220delTAinsCT p.Leu740Ser	missense	N/A	Prot: ENSP00000274008.3 UniProt:
	AFG2A ENST00000422835.2	TSL:1	n.2261_2262delTAinsCT	non_coding_transcript_exon	Exon 14 of 15	Prot:
	AFG2A ENST00000675612.1		c.2288_2289delTAinsCT p.Leu763Ser	missense	N/A	Prot: ENSP00000502453.1 UniProt:

AFG2A ENST00000274008.5

TSL:1MANE Select

HGVSc / HGVSpc.2219_2220delTAinsCTp.Leu740Ser

Exon rankN/A

missense

Prot: ENSP00000274008.3UniProt: Q8NB90-1

AFG2A ENST00000422835.2

TSL:1

HGVSc / HGVSpn.2261_2262delTAinsCT

Exon rankExon 14 of 15

non_coding_transcript_exon

Prot:

AFG2A ENST00000675612.1

HGVSc / HGVSpc.2288_2289delTAinsCTp.Leu763Ser

Exon rankN/A

missense

Prot: ENSP00000502453.1UniProt: A0A6Q8PGU6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	2.6

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr4-124011739;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar