X-130129397-T-C

Variant summary

Our verdict is Benign. Variant got -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

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:):

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIFM1	NM_004208.4	c.*160A>G		3_prime_UTR_variant	16/16	ENST00000287295.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIFM1	ENST00000287295.8	c.*160A>G		3_prime_UTR_variant	16/16	1	NM_004208.4

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 676 AN: 111914 Hom.: 2 Cov.: 23 AF XY: 0.00493 AC XY: 168 AN XY: 34080

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

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.000746

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000445

Gnomad4 OTH exome AF: 0.00201

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

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.00172

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000939

Gnomad4 OTH AF: 0.00327

Alfa AF: 0.00477 Hom.: 12

Bravo AF: 0.00727

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	11
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs189635584; hg19: chrX-129263372;