22-42081937-C-A

Variant names:

• chr22-42081937-C-A
• rs752494247
• NM_033318.5:c.199C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033318.5(SMDT1):​c.199C>A​(p.Leu67Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: SMDT1 NM_033318.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70
• Publications: 0 publications found

Genes affected

SMDT1 (HGNC:25055): (single-pass membrane protein with aspartate rich tail 1) This gene encodes a core regulatory component of a calcium channel in the mitochondrial inner membrane. [provided by RefSeq, Apr 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033318.5. 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
	SMDT1	NM_033318.5	MANE Select	c.199C>A	p.Leu67Ile	missense	Exon 2 of 3	NP_201575.3
	SMDT1	NR_146715.2		n.219C>A		non_coding_transcript_exon	Exon 2 of 3
	SMDT1	NR_146717.1		n.179C>A		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMDT1	ENST00000331479.4	TSL:1 MANE Select	c.199C>A	p.Leu67Ile	missense	Exon 2 of 3	ENSP00000327467.3	Q9H4I9
	SMDT1	ENST00000484235.1	TSL:1	n.268C>A		non_coding_transcript_exon	Exon 2 of 2
	SMDT1	ENST00000924439.1		c.235C>A	p.Leu79Ile	missense	Exon 3 of 4	ENSP00000594498.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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	Benign	0.16
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.26
Sift	Benign	0.12	T
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.70		Loss of helix (P = 0.0558)
MVP		0.65
MPC		1.2
ClinPred		0.83	D
GERP RS		5.8
Varity_R		0.48
gMVP		0.51
Mutation Taster		=46/54	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: rs752494247; hg19: chr22-42477941;