rs761765345

chrX-130130131-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_004208.4(AIFM1):c.1609G>A(p.Glu537Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000884 in 1,210,035 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 38 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 0.000098 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000087 (0 hom. 36 hem.)
• Consequence: AIFM1 NM_004208.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.38

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 (MetaRNN=0.16446835).
• BP6: Variant X-130130131-C-T is Benign according to our data. Variant chrX-130130131-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 543930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIFM1	NM_004208.4	c.1609G>A	p.Glu537Lys	missense_variant	15/16	ENST00000287295.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIFM1	ENST00000287295.8	c.1609G>A	p.Glu537Lys	missense_variant	15/16	1	NM_004208.4

Frequencies

GnomAD3 genomes AF: 0.0000984 AC: 11 AN: 111808 Hom.: 0 Cov.: 23 AF XY: 0.0000589 AC XY: 2 AN XY: 33970

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000951

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000941

Gnomad OTH AF: 0.000670

GnomAD3 exomes AF: 0.000131 AC: 24 AN: 183375 Hom.: 0 AF XY: 0.000162 AC XY: 11 AN XY: 67835

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000937

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000874 AC: 96 AN: 1098227 Hom.: 0 Cov.: 31 AF XY: 0.0000990 AC XY: 36 AN XY: 363587

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000641

Gnomad4 NFE exome AF: 0.0000819

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000984 AC: 11 AN: 111808 Hom.: 0 Cov.: 23 AF XY: 0.0000589 AC XY: 2 AN XY: 33970

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000951

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.0000941

Gnomad4 OTH AF: 0.000670

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2021

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.;.;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.24	T;T;T;T
Sift4G	Benign	0.67	T;T;T;T
Polyphen		0.12, 0.36, 0.25	.;B;B;B
Vest4		0.35
MutPred		0.27		.;.;.;Gain of sheet (P = 0.0028);
MVP		0.85
MPC		0.74
ClinPred		0.12	T
GERP RS		4.9
Varity_R		0.30
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs761765345; hg19: chrX-129264106; COSMIC: COSV54854754;