rs2040862241

Variant names:

• chr17-48931710-C-T
• rs2040862241
• NM_007241.4:c.572G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_007241.4(SNF8):​c.572G>A​(p.Gly191Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SNF8 NM_007241.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.30
• Publications: 1 publications found

Genes affected

SNF8 (HGNC:17028): (SNF8 subunit of ESCRT-II) The protein encoded by this gene is a component of the endosomal sorting complex required for transport II (ESCRT-II), which regulates the movement of ubiquitinylated transmembrane proteins to the lysosome for degradation. This complex also interacts with the RNA polymerase II elongation factor (ELL) to overcome the repressive effects of ELL on RNA polymerase II activity. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

SNF8 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy 115

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• neurodevelopmental disorder plus optic atrophy

  Inheritance: AR Classification: MODERATE Submitted by: G2P, PanelApp Australia
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000230532 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.1333 (below the threshold of 3.09). Trascript score misZ: 1.3894 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder plus optic atrophy, complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 17-48931710-C-T is Pathogenic according to our data. Variant chr17-48931710-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2664479.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007241.4. 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
	SNF8	NM_007241.4	MANE Select	c.572G>A	p.Gly191Asp	missense	Exon 7 of 8	NP_009172.2
	SNF8	NM_001317192.2		c.569G>A	p.Gly190Asp	missense	Exon 7 of 8	NP_001304121.1	Q96H20-2
	SNF8	NM_001317193.2		c.521G>A	p.Gly174Asp	missense	Exon 6 of 7	NP_001304122.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNF8	ENST00000502492.6	TSL:1 MANE Select	c.572G>A	p.Gly191Asp	missense	Exon 7 of 8	ENSP00000421380.1	Q96H20-1
	SNF8	ENST00000290330.7	TSL:1	c.569G>A	p.Gly190Asp	missense	Exon 7 of 8	ENSP00000290330.3	Q96H20-2
	SNF8	ENST00000956813.1		c.659G>A	p.Gly220Asp	missense	Exon 8 of 9	ENSP00000626872.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460370 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726472

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 85910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111236

Other (OTH) AF: 0.0000166 AC: 1 AN: 60342

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy 115 (1)
1	-	-	SNF8-associated disease (1)
1	-	-	SNF8-associated disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.72		Loss of MoRF binding (P = 0.0975)
MVP		0.48
MPC		1.3
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.83
Mutation Taster		=19/81	disease causing

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: rs2040862241; hg19: chr17-47009072;