rs143792929

Variant names:

• chrX-130133432-G-A
• rs143792929
• NM_004208.4:c.1329C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004208.4(AIFM1):​c.1329C>T​(p.Tyr443Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,206,988 control chromosomes in the GnomAD database, including 2 homozygotes. There are 478 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 0.0012 (0 hom., 34 hem., cov: 21)
  • Exomes 𝑓: 0.0013 (2 hom. 444 hem.)
• Consequence: AIFM1 NM_004208.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.344
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant X-130133432-G-A is Benign according to our data. Variant chrX-130133432-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.344 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0012 (131/108977) while in subpopulation NFE AF = 0.00227 (119/52538). AF 95% confidence interval is 0.00193. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 34 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.1329C>T	p.Tyr443Tyr	synonymous	Exon 13 of 16	NP_004199.1
	AIFM1	NM_145812.3		c.1317C>T	p.Tyr439Tyr	synonymous	Exon 13 of 16	NP_665811.1
	AIFM1	NM_001130846.4		c.312C>T	p.Tyr104Tyr	synonymous	Exon 4 of 7	NP_001124318.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIFM1	ENST00000287295.8	TSL:1 MANE Select	c.1329C>T	p.Tyr443Tyr	synonymous	Exon 13 of 16	ENSP00000287295.3
	AIFM1	ENST00000675092.1		c.1329C>T	p.Tyr443Tyr	synonymous	Exon 13 of 16	ENSP00000501772.1
	AIFM1	ENST00000319908.8	TSL:1	c.1326C>T	p.Tyr442Tyr	synonymous	Exon 13 of 16	ENSP00000315122.4

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 131 AN: 108977 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000268

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: 0.000732

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00227

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000839 AC: 154 AN: 183462 AF XY: 0.000825

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000375

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.00127 AC: 1395 AN: 1098011 Hom.: 2 Cov.: 31 AF XY: 0.00122 AC XY: 444 AN XY: 363367

African (AFR) AF: 0.000303 AC: 8 AN: 26396

American (AMR) AF: 0.000142 AC: 5 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54142

European-Finnish (FIN) AF: 0.000494 AC: 20 AN: 40514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00156 AC: 1316 AN: 841949

Other (OTH) AF: 0.000933 AC: 43 AN: 46087

GnomAD4 genome AF: 0.00120 AC: 131 AN: 108977 Hom.: 0 Cov.: 21 AF XY: 0.00108 AC XY: 34 AN XY: 31459

African (AFR) AF: 0.000268 AC: 8 AN: 29844

American (AMR) AF: 0.00 AC: 0 AN: 10126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3509

South Asian (SAS) AF: 0.00 AC: 0 AN: 2505

European-Finnish (FIN) AF: 0.000732 AC: 4 AN: 5461

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00227 AC: 119 AN: 52538

Other (OTH) AF: 0.00 AC: 0 AN: 1453

Alfa AF: 0.000909 Hom.: 7

Bravo AF: 0.000865

EpiCase AF: 0.00136

EpiControl AF: 0.00130

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	Severe X-linked mitochondrial encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.4
DANN	Benign	0.48
PhyloP100		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	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: rs143792929; hg19: chrX-129267407; COSMIC: COSV54857272; COSMIC: COSV54857272;