22-20973825-C-T

Variant names:

• chr22-20973825-C-T
• rs375928890
• NM_001386814.1:c.313C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001386814.1(AIFM3):​c.313C>T​(p.Leu105Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,427,654 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AIFM3 NM_001386814.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29
• Publications: 0 publications found

Genes affected

AIFM3 (HGNC:26398): (apoptosis inducing factor mitochondria associated 3) Predicted to enable several functions, including 2 iron, 2 sulfur cluster binding activity; flavin adenine dinucleotide binding activity; and metal ion binding activity. Involved in execution phase of apoptosis. Located in cytosol; endoplasmic reticulum; and mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386814.1. 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
	AIFM3	NM_001386814.1	MANE Select	c.313C>T	p.Leu105Leu	synonymous	Exon 4 of 21	NP_001373743.1	Q96NN9-1
	AIFM3	NM_144704.3		c.313C>T	p.Leu105Leu	synonymous	Exon 4 of 21	NP_653305.1	Q96NN9-1
	AIFM3	NM_001146288.2		c.331C>T	p.Leu111Leu	synonymous	Exon 4 of 20	NP_001139760.1	Q96NN9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIFM3	ENST00000440238.4	TSL:1 MANE Select	c.313C>T	p.Leu105Leu	synonymous	Exon 4 of 21	ENSP00000390798.2	Q96NN9-1
	AIFM3	ENST00000399163.6	TSL:1	c.313C>T	p.Leu105Leu	synonymous	Exon 4 of 20	ENSP00000382116.2	Q96NN9-3
	AIFM3	ENST00000399167.6	TSL:2	c.313C>T	p.Leu105Leu	synonymous	Exon 4 of 21	ENSP00000382120.2	Q96NN9-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000102 AC: 2 AN: 196874 AF XY: 0.00000951

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000693

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1427654 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 706722

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32910

American (AMR) AF: 0.0000500 AC: 2 AN: 40006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 38288

South Asian (SAS) AF: 0.00 AC: 0 AN: 80778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5456

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094848

Other (OTH) AF: 0.00 AC: 0 AN: 59062

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.8
DANN	Benign	0.85
PhyloP100		1.3

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: rs375928890; hg19: chr22-21328114;