NM_015110.4:c.1051C>A

Variant names:

• chr9-70286269-C-A
• rs760641227
• NM_015110.4:c.1051C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015110.4(SMC5):​c.1051C>A​(p.His351Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000697 in 143,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMC5 NM_015110.4 missense, splice_region
• Scores: Splicing: ADA: 0.007742
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13
• Publications: 0 publications found

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]

SMC5 Gene-Disease associations (from GenCC):

• Atelis syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050124764).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015110.4. 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
	SMC5	NM_015110.4	MANE Select	c.1051C>A	p.His351Asn	missense splice_region	Exon 8 of 25	NP_055925.2	Q8IY18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC5	ENST00000361138.7	TSL:1 MANE Select	c.1051C>A	p.His351Asn	missense splice_region	Exon 8 of 25	ENSP00000354957.5	Q8IY18
	SMC5	ENST00000912980.1		c.1051C>A	p.His351Asn	missense splice_region	Exon 8 of 26	ENSP00000583039.1
	SMC5	ENST00000884400.1		c.1051C>A	p.His351Asn	missense splice_region	Exon 8 of 24	ENSP00000554459.1

Frequencies

GnomAD3 genomes AF: 0.00000697 AC: 1 AN: 143504 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000173 AC: 4 AN: 231178 AF XY: 0.0000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.0000281

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000176 AC: 24 AN: 1367476 Hom.: 0 Cov.: 27 AF XY: 0.0000191 AC XY: 13 AN XY: 680852

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30050

American (AMR) AF: 0.0000258 AC: 1 AN: 38802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23302

East Asian (EAS) AF: 0.00 AC: 0 AN: 33298

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5410

European-Non Finnish (NFE) AF: 0.0000180 AC: 19 AN: 1053286

Other (OTH) AF: 0.0000363 AC: 2 AN: 55062

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000252280), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000697 AC: 1 AN: 143504 Hom.: 0 Cov.: 31 AF XY: 0.0000145 AC XY: 1 AN XY: 68964

African (AFR) AF: 0.00 AC: 0 AN: 38468

American (AMR) AF: 0.00 AC: 0 AN: 13308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 4760

South Asian (SAS) AF: 0.00 AC: 0 AN: 4594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 66892

Other (OTH) AF: 0.00 AC: 0 AN: 1950

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N
PhyloP100		1.1
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.025
Sift	Benign	0.17	T
Sift4G	Benign	0.16	T
Polyphen		0.061	B
Vest4		0.18
MutPred		0.24		Gain of MoRF binding (P = 0.104)
MVP		0.15
MPC		0.18
ClinPred		0.14	T
GERP RS		5.2
Varity_R		0.070
gMVP		0.19
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0077
dbscSNV1_RF	Benign	0.14
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: rs760641227; hg19: chr9-72901185;