rs61730896

Variant names:

• chrX-130165554-G-A
• rs61730896
• NM_004208.4:c.103C>T

Variant summary

Our verdict is Benign. The variant received -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. 12/20 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:8
• Conservation: PhyloP100: 1.47
• Publications: 5 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 -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 Benign/Likely_benign. ClinVar VariationId is 136326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.103C>T	p.Pro35Ser	missense	Exon 1 of 16	NP_004199.1
	AIFM1	NM_145812.3		c.103C>T	p.Pro35Ser	missense	Exon 1 of 16	NP_665811.1
	AIFM1	NM_001130847.4		c.103C>T	p.Pro35Ser	missense	Exon 1 of 17	NP_001124319.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIFM1	ENST00000287295.8	TSL:1 MANE Select	c.103C>T	p.Pro35Ser	missense	Exon 1 of 16	ENSP00000287295.3
	AIFM1	ENST00000675092.1		c.103C>T	p.Pro35Ser	missense	Exon 1 of 16	ENSP00000501772.1
	AIFM1	ENST00000319908.8	TSL:1	c.103C>T	p.Pro35Ser	missense	Exon 1 of 16	ENSP00000315122.4

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 520 AN: 112737 Hom.: 3 Cov.: 24

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

GnomAD2 exomes AF: 0.00136 AC: 192 AN: 141189 AF XY: 0.000932

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 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

African (AFR) AF: 0.0194 AC: 502 AN: 25941

American (AMR) AF: 0.00107 AC: 35 AN: 32584

Ashkenazi Jewish (ASJ) AF: 0.0000528 AC: 1 AN: 18933

East Asian (EAS) AF: 0.00 AC: 0 AN: 29067

South Asian (SAS) AF: 0.0000389 AC: 2 AN: 51473

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38906

Middle Eastern (MID) AF: 0.00219 AC: 9 AN: 4105

European-Non Finnish (NFE) AF: 0.0000241 AC: 20 AN: 830302

Other (OTH) AF: 0.00153 AC: 69 AN: 45214

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

African (AFR) AF: 0.0160 AC: 498 AN: 31128

American (AMR) AF: 0.00102 AC: 11 AN: 10735

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3591

South Asian (SAS) AF: 0.000366 AC: 1 AN: 2735

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6212

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.0000563 AC: 3 AN: 53290

Other (OTH) AF: 0.00453 AC: 7 AN: 1546

Alfa AF: 0.000928 Hom.: 58

Bravo AF: 0.00557

ESP6500AA AF: 0.0149 AC: 57

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00134 AC: 159

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease X-linked recessive 4;C1845095:Deafness, X-linked 5;C1846148:Spondyloepimetaphyseal dysplasia, Bieganski type;C3151753:Severe X-linked mitochondrial encephalomyopathy (1)
-	-	1	Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X (1)
-	-	1	Severe X-linked mitochondrial encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.022
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.040	D
Polyphen		0.31	B
Vest4		0.41
MVP		0.88
MPC		0.65
ClinPred		0.012	T
GERP RS		2.8
PromoterAI		0.096	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.096
gMVP		0.54
Mutation Taster		=97/3	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: rs61730896; hg19: chrX-129299528;