9-70264335-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_015110.4(SMC5):​c.217C>T​(p.Pro73Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,612 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: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SMC5
NM_015110.4 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.68
Variant links:
Genes affected
SMC5 (HGNC:20465): (structural maintenance of chromosomes 5) Predicted to enable ATP binding activity. Involved in several processes, including DNA recombination; cellular senescence; and positive regulation of maintenance of mitotic sister chromatid cohesion. Located in cell junction; chromosome; and nuclear body. Part of Smc5-Smc6 complex. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SMC5NM_015110.4 linkuse as main transcriptc.217C>T p.Pro73Ser missense_variant 2/25 ENST00000361138.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SMC5ENST00000361138.7 linkuse as main transcriptc.217C>T p.Pro73Ser missense_variant 2/251 NM_015110.4 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461612
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727128
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 15, 2023The c.217C>T (p.P73S) alteration is located in exon 2 (coding exon 2) of the SMC5 gene. This alteration results from a C to T substitution at nucleotide position 217, causing the proline (P) at amino acid position 73 to be replaced by a serine (S). 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
Benign
0.25
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.27
T
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.080
D
MetaRNN
Pathogenic
0.79
D
MetaSVM
Uncertain
0.11
D
MutationAssessor
Uncertain
2.5
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-4.8
D
REVEL
Uncertain
0.54
Sift
Uncertain
0.028
D
Sift4G
Benign
0.22
T
Polyphen
1.0
D
Vest4
0.63
MutPred
0.58
Gain of catalytic residue at P73 (P = 0.0373);
MVP
0.56
MPC
0.65
ClinPred
0.99
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.37
gMVP
0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-72879251; API