X-130129397-T-C

Variant names:

• chrX-130129397-T-C
• rs189635584
• NM_004208.4:c.*160A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004208.4(AIFM1):​c.*160A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 494,807 control chromosomes in the GnomAD database, including 8 homozygotes. There are 243 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 0.0060 (2 hom., 168 hem., cov: 23)
  • Exomes 𝑓: 0.00079 (6 hom. 75 hem.)
• Consequence: AIFM1 NM_004208.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.58
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant X-130129397-T-C is Benign according to our data. Variant chrX-130129397-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1197495.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00603 (675/111969) while in subpopulation AFR AF = 0.0209 (646/30871). AF 95% confidence interval is 0.0196. There are 2 homozygotes in GnomAd4. There are 168 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.*160A>G		3_prime_UTR	Exon 16 of 16	NP_004199.1	O95831-1
	AIFM1	NM_145812.3		c.*160A>G		3_prime_UTR	Exon 16 of 16	NP_665811.1	O95831-3
	AIFM1	NM_001130847.4		c.*1230A>G		3_prime_UTR	Exon 17 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.*160A>G		3_prime_UTR	Exon 16 of 16	ENSP00000287295.3	O95831-1
	AIFM1	ENST00000675092.1		c.*160A>G		3_prime_UTR	Exon 16 of 16	ENSP00000501772.1	A0A6Q8PFE1
	AIFM1	ENST00000319908.8	TSL:1	c.*160A>G		3_prime_UTR	Exon 16 of 16	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 676 AN: 111914 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00172

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.0000939

Gnomad OTH AF: 0.00331

GnomAD4 exome AF: 0.000786 AC: 301 AN: 382838 Hom.: 6 Cov.: 5 AF XY: 0.000583 AC XY: 75 AN XY: 128610

African (AFR) AF: 0.0211 AC: 239 AN: 11311

American (AMR) AF: 0.000746 AC: 17 AN: 22774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12433

East Asian (EAS) AF: 0.00 AC: 0 AN: 23932

South Asian (SAS) AF: 0.00 AC: 0 AN: 32201

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2750

European-Non Finnish (NFE) AF: 0.00000445 AC: 1 AN: 224563

Other (OTH) AF: 0.00201 AC: 44 AN: 21846

GnomAD4 genome AF: 0.00603 AC: 675 AN: 111969 Hom.: 2 Cov.: 23 AF XY: 0.00492 AC XY: 168 AN XY: 34145

African (AFR) AF: 0.0209 AC: 646 AN: 30871

American (AMR) AF: 0.00172 AC: 18 AN: 10483

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2677

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6058

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.0000939 AC: 5 AN: 53224

Other (OTH) AF: 0.00327 AC: 5 AN: 1529

Alfa AF: 0.00477 Hom.: 12

Bravo AF: 0.00727

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs189635584; hg19: chrX-129263372;