9-121353258-C-T

Variant names:

• chr9-121353258-C-T
• NM_004099.6:c.283G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004099.6(STOM):​c.283G>A​(p.Asp95Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,459,616 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: STOM NM_004099.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71
• Publications: 0 publications found

Genes affected

STOM (HGNC:3383): (stomatin) This gene encodes a member of a highly conserved family of integral membrane proteins. The encoded protein localizes to the cell membrane of red blood cells and other cell types, where it may regulate ion channels and transporters. Loss of localization of the encoded protein is associated with hereditary stomatocytosis, a form of hemolytic anemia. There is a pseudogene for this gene on chromosome 6. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004099.6. 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
	STOM	NM_004099.6	MANE Select	c.283G>A	p.Asp95Asn	missense	Exon 4 of 7	NP_004090.4
	STOM	NM_001270526.2		c.283G>A	p.Asp95Asn	missense	Exon 4 of 7	NP_001257455.1
	STOM	NM_001270527.2		c.283G>A	p.Asp95Asn	missense	Exon 4 of 6	NP_001257456.1	F8VSL7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STOM	ENST00000286713.7	TSL:1 MANE Select	c.283G>A	p.Asp95Asn	missense	Exon 4 of 7	ENSP00000286713.2	P27105-1
	STOM	ENST00000965234.1		c.346G>A	p.Asp116Asn	missense	Exon 5 of 8	ENSP00000635293.1
	STOM	ENST00000965235.1		c.283G>A	p.Asp95Asn	missense	Exon 4 of 7	ENSP00000635294.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1459616 Hom.: 0 Cov.: 29 AF XY: 0.00000964 AC XY: 7 AN XY: 726100

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.00 AC: 0 AN: 85848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111028

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.92
MutPred		0.88		Gain of methylation at K93 (P = 0.0875)
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.76
Mutation Taster		=5/95	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

hg19: chr9-124115536;