rs141324245

Variant names:

• chrX-130133345-A-G
• rs141324245
• NM_004208.4:c.1416T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004208.4(AIFM1):​c.1416T>C​(p.Ala472Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00051 in 1,209,289 control chromosomes in the GnomAD database, including 1 homozygotes. There are 179 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., 81 hem., cov: 22)
  • Exomes 𝑓: 0.00031 (1 hom. 98 hem.)
• Consequence: AIFM1 NM_004208.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.11
• Publications: 1 publications found

Genes affected

AIFM1 (HGNC:8768): (apoptosis inducing factor mitochondria associated 1) This gene encodes a flavoprotein essential for nuclear disassembly in apoptotic cells, and it is found in the mitochondrial intermembrane space in healthy cells. Induction of apoptosis results in the translocation of this protein to the nucleus where it affects chromosome condensation and fragmentation. In addition, this gene product induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Mutations in this gene cause combined oxidative phosphorylation deficiency 6 (COXPD6), a severe mitochondrial encephalomyopathy, as well as Cowchock syndrome, also known as X-linked recessive Charcot-Marie-Tooth disease-4 (CMTX-4), a disorder resulting in neuropathy, and axonal and motor-sensory defects with deafness and cognitive disability. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 10. [provided by RefSeq, Aug 2015]

RAB33A (HGNC:9773): (RAB33A, member RAS oncogene family) The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. It is GTP-binding protein and may be involved in vesicle transport. [provided by RefSeq, Jul 2008]

ENSG00000286650 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-130133345-A-G is Benign according to our data. Variant chrX-130133345-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00249 (277/111128) while in subpopulation AFR AF = 0.00857 (262/30582). AF 95% confidence interval is 0.00772. There are 0 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 81 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004208.4. 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
	AIFM1	NM_004208.4	MANE Select	c.1416T>C	p.Ala472Ala	synonymous	Exon 13 of 16	NP_004199.1	O95831-1
	AIFM1	NM_145812.3		c.1404T>C	p.Ala468Ala	synonymous	Exon 13 of 16	NP_665811.1	O95831-3
	AIFM1	NM_001130846.4		c.399T>C	p.Ala133Ala	synonymous	Exon 4 of 7	NP_001124318.2	E9PMA0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIFM1	ENST00000287295.8	TSL:1 MANE Select	c.1416T>C	p.Ala472Ala	synonymous	Exon 13 of 16	ENSP00000287295.3	O95831-1
	AIFM1	ENST00000675092.1		c.1416T>C	p.Ala472Ala	synonymous	Exon 13 of 16	ENSP00000501772.1	A0A6Q8PFE1
	AIFM1	ENST00000319908.8	TSL:1	c.1413T>C	p.Ala471Ala	synonymous	Exon 13 of 16	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 277 AN: 111074 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00859

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000961

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000943

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000676 AC: 124 AN: 183396 AF XY: 0.000531

Gnomad AFR exome AF: 0.00790

Gnomad AMR exome AF: 0.000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000310 AC: 340 AN: 1098161 Hom.: 1 Cov.: 31 AF XY: 0.000270 AC XY: 98 AN XY: 363531

African (AFR) AF: 0.00848 AC: 224 AN: 26402

American (AMR) AF: 0.000625 AC: 22 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000867 AC: 73 AN: 842060

Other (OTH) AF: 0.000434 AC: 20 AN: 46094

GnomAD4 genome AF: 0.00249 AC: 277 AN: 111128 Hom.: 0 Cov.: 22 AF XY: 0.00243 AC XY: 81 AN XY: 33328

African (AFR) AF: 0.00857 AC: 262 AN: 30582

American (AMR) AF: 0.000960 AC: 10 AN: 10420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3526

South Asian (SAS) AF: 0.00 AC: 0 AN: 2621

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000943 AC: 5 AN: 53019

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.00214 Hom.: 4

Bravo AF: 0.00296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	AIFM1-related disorder (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	Severe X-linked mitochondrial encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.68
PhyloP100		2.1
Mutation Taster		=99/1	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: rs141324245; hg19: chrX-129267320;