rs61730896

chrX-130165554-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004208.4(AIFM1):c.103C>T(p.Pro35Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000975 in 1,189,312 control chromosomes in the GnomAD database, including 6 homozygotes. There are 322 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., 153 hem., cov: 24)
  • Exomes 𝑓: 0.00059 (3 hom. 169 hem.)
• Consequence: AIFM1 NM_004208.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.47

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008270264).
• BP6: Variant X-130165554-G-A is Benign according to our data. Variant chrX-130165554-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-130165554-G-A is described in Lovd as [Likely_benign]. Variant chrX-130165554-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00462 (521/112787) while in subpopulation AFR AF= 0.016 (498/31128). AF 95% confidence interval is 0.0148. There are 3 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIFM1	NM_004208.4	c.103C>T	p.Pro35Ser	missense_variant	1/16	ENST00000287295.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIFM1	ENST00000287295.8	c.103C>T	p.Pro35Ser	missense_variant	1/16	1	NM_004208.4

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 520 AN: 112737 Hom.: 3 Cov.: 24 AF XY: 0.00436 AC XY: 152 AN XY: 34885

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000364

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0000563

Gnomad OTH AF: 0.00458

GnomAD3 exomes AF: 0.00136 AC: 192 AN: 141189 Hom.: 1 AF XY: 0.000932 AC XY: 41 AN XY: 44007

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.000755

Gnomad ASJ exome AF: 0.000149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000643

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000348

Gnomad OTH exome AF: 0.00162

GnomAD4 exome AF: 0.000593 AC: 638 AN: 1076525 Hom.: 3 Cov.: 30 AF XY: 0.000481 AC XY: 169 AN XY: 351005

Gnomad4 AFR exome AF: 0.0194

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.0000528

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000389

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000241

Gnomad4 OTH exome AF: 0.00153

GnomAD4 genome AF: 0.00462 AC: 521 AN: 112787 Hom.: 3 Cov.: 24 AF XY: 0.00438 AC XY: 153 AN XY: 34945

Gnomad4 AFR AF: 0.0160

Gnomad4 AMR AF: 0.00102

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000366

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000563

Gnomad4 OTH AF: 0.00453

Alfa AF: 0.000506 Hom.: 18

Bravo AF: 0.00557

ESP6500AA AF: 0.0149 AC: 57

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00134 AC: 159

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Charcot-Marie-Tooth disease X-linked recessive 4;C1845095:Deafness, X-linked 5;C1846148:Spondyloepimetaphyseal dysplasia, Bieganski type;C3151753:Severe X-linked mitochondrial encephalomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 15, 2021

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Severe X-linked mitochondrial encephalomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	17
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.48	T;T;.;T
MetaRNN	Benign	0.0083	T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.1	M;M;M;M
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.47	N;N;.;N
REVEL	Benign	0.022
Sift	Uncertain	0.012	D;T;.;T
Sift4G	Uncertain	0.040	D;T;T;T
Polyphen		0.31	B;B;.;B
Vest4		0.41
MVP		0.88
MPC		0.65
ClinPred		0.012	T
GERP RS		2.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.096
gMVP		0.54

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: rs61730896; hg19: chrX-129299528;