chrX-130129824-C-T

Variant names:

• chrX-130129824-C-T
• rs112112387
• NM_004208.4:c.1770+146G>A

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.1770+146G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 843,774 control chromosomes in the GnomAD database, including 12 homozygotes. There are 226 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 0.0047 (5 hom., 138 hem., cov: 23)
  • Exomes 𝑓: 0.00052 (7 hom. 88 hem.)
• Consequence: AIFM1 NM_004208.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.228
• 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=-0.57).
• BP6: Variant X-130129824-C-T is Benign according to our data. Variant chrX-130129824-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1216339.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00475 (532/112006) while in subpopulation AFR AF = 0.0167 (514/30866). AF 95% confidence interval is 0.0155. There are 5 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.1770+146G>A		intron	N/A	NP_004199.1	O95831-1
	AIFM1	NM_145812.3		c.1758+146G>A		intron	N/A	NP_665811.1	O95831-3
	AIFM1	NM_001130847.4		c.*998+146G>A		intron	N/A	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.1770+146G>A		intron	N/A	ENSP00000287295.3	O95831-1
	AIFM1	ENST00000675092.1		c.1797+146G>A		intron	N/A	ENSP00000501772.1	A0A6Q8PFE1
	AIFM1	ENST00000319908.8	TSL:1	c.1764+146G>A		intron	N/A	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes AF: 0.00475 AC: 532 AN: 111951 Hom.: 5 Cov.: 23

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.0000188

Gnomad OTH AF: 0.00267

GnomAD4 exome AF: 0.000521 AC: 381 AN: 731768 Hom.: 7 AF XY: 0.000429 AC XY: 88 AN XY: 205316

African (AFR) AF: 0.0157 AC: 298 AN: 18986

American (AMR) AF: 0.00100 AC: 32 AN: 31982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16708

East Asian (EAS) AF: 0.00 AC: 0 AN: 27760

South Asian (SAS) AF: 0.0000223 AC: 1 AN: 44917

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37715

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2401

European-Non Finnish (NFE) AF: 0.00000386 AC: 2 AN: 517512

Other (OTH) AF: 0.00142 AC: 48 AN: 33787

GnomAD4 genome AF: 0.00475 AC: 532 AN: 112006 Hom.: 5 Cov.: 23 AF XY: 0.00404 AC XY: 138 AN XY: 34180

African (AFR) AF: 0.0167 AC: 514 AN: 30866

American (AMR) AF: 0.00123 AC: 13 AN: 10537

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2689

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6122

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

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53167

Other (OTH) AF: 0.00264 AC: 4 AN: 1515

Alfa AF: 0.00356 Hom.: 7

Bravo AF: 0.00505

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	-0.57
CADD	Benign	12
DANN	Benign	0.89
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs112112387; hg19: chrX-129263799;