X-130129566-A-G

Variant names:

• chrX-130129566-A-G
• rs73556209
• NM_004208.4:c.1833T>C

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.1833T>C​(p.His611His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,208,751 control chromosomes in the GnomAD database, including 6 homozygotes. There are 348 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 0.0051 (2 hom., 154 hem., cov: 23)
  • Exomes 𝑓: 0.00064 (4 hom. 194 hem.)
• Consequence: AIFM1 NM_004208.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.112
• 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=-0.53).
• BP6: Variant X-130129566-A-G is Benign according to our data. Variant chrX-130129566-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.112 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00511 (570/111573) while in subpopulation AFR AF = 0.0177 (543/30706). AF 95% confidence interval is 0.0165. There are 2 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1833T>C	p.His611His	synonymous	Exon 16 of 16	NP_004199.1
	AIFM1	NM_145812.3		c.1821T>C	p.His607His	synonymous	Exon 16 of 16	NP_665811.1
	AIFM1	NM_001130846.4		c.816T>C	p.His272His	synonymous	Exon 7 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.1833T>C	p.His611His	synonymous	Exon 16 of 16	ENSP00000287295.3
	AIFM1	ENST00000675092.1		c.1860T>C	p.His620His	synonymous	Exon 16 of 16	ENSP00000501772.1
	AIFM1	ENST00000319908.8	TSL:1	c.1827T>C	p.His609His	synonymous	Exon 16 of 16	ENSP00000315122.4

Frequencies

GnomAD3 genomes AF: 0.00510 AC: 569 AN: 111519 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00172

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000377

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000941

Gnomad OTH AF: 0.00200

GnomAD2 exomes AF: 0.00158 AC: 290 AN: 183490 AF XY: 0.00106

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.000911

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000610

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000643 AC: 705 AN: 1097178 Hom.: 4 Cov.: 29 AF XY: 0.000535 AC XY: 194 AN XY: 362560

African (AFR) AF: 0.0201 AC: 529 AN: 26380

American (AMR) AF: 0.000937 AC: 33 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.000148 AC: 8 AN: 54124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.000725 AC: 3 AN: 4137

European-Non Finnish (NFE) AF: 0.0000963 AC: 81 AN: 841163

Other (OTH) AF: 0.00111 AC: 51 AN: 46060

GnomAD4 genome AF: 0.00511 AC: 570 AN: 111573 Hom.: 2 Cov.: 23 AF XY: 0.00456 AC XY: 154 AN XY: 33759

African (AFR) AF: 0.0177 AC: 543 AN: 30706

American (AMR) AF: 0.00171 AC: 18 AN: 10500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3553

South Asian (SAS) AF: 0.000379 AC: 1 AN: 2642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6003

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

European-Non Finnish (NFE) AF: 0.0000942 AC: 5 AN: 53106

Other (OTH) AF: 0.00197 AC: 3 AN: 1521

Alfa AF: 0.00291 Hom.: 14

Bravo AF: 0.00617

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease X-linked recessive 4;C1845095:Deafness, X-linked 5;C1846148:Spondyloepimetaphyseal dysplasia, Bieganski type;C3151753:Severe X-linked mitochondrial encephalomyopathy (1)
-	-	1	Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Severe X-linked mitochondrial encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.55
DANN	Benign	0.69
PhyloP100		-0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs73556209; hg19: chrX-129263541;