rs373609902

Variant names:

• chrX-130165585-G-A
• rs373609902
• NM_004208.4:c.72C>T

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.72C>T​(p.Cys24Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000673 in 1,199,365 control chromosomes in the GnomAD database, including 2 homozygotes. There are 234 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 0.00049 (0 hom., 14 hem., cov: 24)
  • Exomes 𝑓: 0.00069 (2 hom. 220 hem.)
• Consequence: AIFM1 NM_004208.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.96
• Publications: 0 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=-0.27).
• BP6: Variant X-130165585-G-A is Benign according to our data. Variant chrX-130165585-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 367894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000489 (55/112579) while in subpopulation NFE AF = 0.000921 (49/53212). AF 95% confidence interval is 0.000715. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 14 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.72C>T	p.Cys24Cys	synonymous	Exon 1 of 16	NP_004199.1	O95831-1
	AIFM1	NM_145812.3		c.72C>T	p.Cys24Cys	synonymous	Exon 1 of 16	NP_665811.1	O95831-3
	AIFM1	NM_001130847.4		c.72C>T	p.Cys24Cys	synonymous	Exon 1 of 17	NP_001124319.1	O95831-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIFM1	ENST00000287295.8	TSL:1 MANE Select	c.72C>T	p.Cys24Cys	synonymous	Exon 1 of 16	ENSP00000287295.3	O95831-1
	AIFM1	ENST00000675092.1		c.72C>T	p.Cys24Cys	synonymous	Exon 1 of 16	ENSP00000501772.1	A0A6Q8PFE1
	AIFM1	ENST00000319908.8	TSL:1	c.72C>T	p.Cys24Cys	synonymous	Exon 1 of 16	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes AF: 0.000489 AC: 55 AN: 112526 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000324

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000921

Gnomad OTH AF: 0.000660

GnomAD2 exomes AF: 0.000301 AC: 47 AN: 156137 AF XY: 0.000325

Gnomad AFR exome AF: 0.000180

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000448

Gnomad NFE exome AF: 0.000560

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.000692 AC: 752 AN: 1086786 Hom.: 2 Cov.: 30 AF XY: 0.000619 AC XY: 220 AN XY: 355588

African (AFR) AF: 0.000115 AC: 3 AN: 26155

American (AMR) AF: 0.00 AC: 0 AN: 34110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19147

East Asian (EAS) AF: 0.00 AC: 0 AN: 29659

South Asian (SAS) AF: 0.00 AC: 0 AN: 52441

European-Finnish (FIN) AF: 0.000355 AC: 14 AN: 39480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.000860 AC: 719 AN: 836054

Other (OTH) AF: 0.000351 AC: 16 AN: 45618

GnomAD4 genome AF: 0.000489 AC: 55 AN: 112579 Hom.: 0 Cov.: 24 AF XY: 0.000403 AC XY: 14 AN XY: 34765

African (AFR) AF: 0.0000966 AC: 3 AN: 31062

American (AMR) AF: 0.00 AC: 0 AN: 10727

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3582

South Asian (SAS) AF: 0.00 AC: 0 AN: 2729

European-Finnish (FIN) AF: 0.000324 AC: 2 AN: 6176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000921 AC: 49 AN: 53212

Other (OTH) AF: 0.000652 AC: 1 AN: 1534

Alfa AF: 0.000695 Hom.: 6

Bravo AF: 0.000400

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X (1)
-	-	1	Severe X-linked mitochondrial encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	13
DANN	Benign	0.95
PhyloP100		3.0
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Mutation Taster		=288/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs373609902; hg19: chrX-129299559; COSMIC: COSV99781009;