22-31083286-G-C

Variant names:

• chr22-31083286-G-C
• rs999367724
• NM_134269.3:c.28G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_134269.3(SMTN):​c.28G>C​(p.Asp10His) variant causes a missense change. The variant allele was found at a frequency of 0.000000697 in 1,434,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SMTN NM_134269.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87

Genes affected

SMTN (HGNC:11126): (smoothelin) This gene encodes a structural protein that is found exclusively in contractile smooth muscle cells. It associates with stress fibers and constitutes part of the cytoskeleton. This gene is localized to chromosome 22q12.3, distal to the TUPLE1 locus and outside the DiGeorge syndrome deletion. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2011]

ENSG00000273387 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2676067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMTN	NM_134269.3	c.28G>C	p.Asp10His	missense_variant	Exon 2 of 21	ENST00000333137.12	NP_599031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMTN	ENST00000333137.12	c.28G>C	p.Asp10His	missense_variant	Exon 2 of 21	1	NM_134269.3	ENSP00000329532.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 711006

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.190G>C (p.D64H) alteration is located in exon 2 (coding exon 2) of the SMTN gene. This alteration results from a G to C substitution at nucleotide position 190, causing the aspartic acid (D) at amino acid position 64 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	.;T;.;.;.;T;.;.;.
Eigen	Benign	0.090
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	.;.;.;.;N;N;N;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.0	D;D;D;D;N;N;N;.;.
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;T;T;T;D;T
Polyphen		1.0	.;.;.;.;.;D;D;.;.
Vest4		0.80, 0.68, 0.84, 0.87
MutPred		0.28		.;Loss of disorder (P = 0.1123);.;.;Loss of disorder (P = 0.1123);Loss of disorder (P = 0.1123);Loss of disorder (P = 0.1123);Loss of disorder (P = 0.1123);.;
MVP		0.20
MPC		0.73
ClinPred		0.99	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.59

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: rs999367724; hg19: chr22-31479272;