rs61730898

Variant names:

• chrX-130136123-A-C
• rs61730898
• NM_004208.4:c.1227T>G

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.1227T>G​(p.Thr409Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,210,236 control chromosomes in the GnomAD database, including 2 homozygotes. There are 102 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 0.0017 (1 hom., 53 hem., cov: 23)
  • Exomes 𝑓: 0.00018 (1 hom. 49 hem.)
• Consequence: AIFM1 NM_004208.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.181
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant X-130136123-A-C is Benign according to our data. Variant chrX-130136123-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 543932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.181 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00172 (193/112125) while in subpopulation AFR AF = 0.00614 (190/30935). AF 95% confidence interval is 0.00543. There are 1 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 53 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.1227T>G	p.Thr409Thr	synonymous	Exon 12 of 16	NP_004199.1
	AIFM1	NM_145812.3		c.1215T>G	p.Thr405Thr	synonymous	Exon 12 of 16	NP_665811.1
	AIFM1	NM_001130846.4		c.210T>G	p.Thr70Thr	synonymous	Exon 3 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.1227T>G	p.Thr409Thr	synonymous	Exon 12 of 16	ENSP00000287295.3
	AIFM1	ENST00000675092.1		c.1227T>G	p.Thr409Thr	synonymous	Exon 12 of 16	ENSP00000501772.1
	AIFM1	ENST00000319908.8	TSL:1	c.1224T>G	p.Thr408Thr	synonymous	Exon 12 of 16	ENSP00000315122.4

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 193 AN: 112071 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.00616

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000284

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000605 AC: 111 AN: 183480 AF XY: 0.000309

Gnomad AFR exome AF: 0.00745

Gnomad AMR exome AF: 0.000437

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: 0.000221

GnomAD4 exome AF: 0.000176 AC: 193 AN: 1098111 Hom.: 1 Cov.: 32 AF XY: 0.000135 AC XY: 49 AN XY: 363467

African (AFR) AF: 0.00621 AC: 164 AN: 26402

American (AMR) AF: 0.000369 AC: 13 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54144

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

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4118

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 842027

Other (OTH) AF: 0.000282 AC: 13 AN: 46090

GnomAD4 genome AF: 0.00172 AC: 193 AN: 112125 Hom.: 1 Cov.: 23 AF XY: 0.00155 AC XY: 53 AN XY: 34283

African (AFR) AF: 0.00614 AC: 190 AN: 30935

American (AMR) AF: 0.000284 AC: 3 AN: 10581

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53177

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.000781 Hom.: 3

Bravo AF: 0.00207

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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 provided (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	7.8
DANN	Benign	0.64
PhyloP100		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=96/4	polymorphism

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: rs61730898; hg19: chrX-129270098;