rs117771893

Positions:

• chr18-2700615-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015295.3(SMCHD1):​c.1419A>G​(p.Glu473=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,611,754 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (28 hom.)
• Consequence: SMCHD1 NM_015295.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.855

Genes affected

SMCHD1 (HGNC:29090): (structural maintenance of chromosomes flexible hinge domain containing 1) This gene encodes a protein which contains a hinge region domain found in members of the SMC (structural maintenance of chromosomes) protein family. [provided by RefSeq, Dec 2011]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 18-2700615-A-G is Benign according to our data. Variant chr18-2700615-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 260629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2700615-A-G is described in Lovd as [Likely_benign]. Variant chr18-2700615-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.855 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00418 (636/152326) while in subpopulation NFE AF= 0.00495 (337/68024). AF 95% confidence interval is 0.00452. There are 2 homozygotes in gnomad4. There are 341 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 636 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMCHD1	NM_015295.3	c.1419A>G	p.Glu473=	synonymous_variant	11/48	ENST00000320876.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCHD1	ENST00000320876.11	c.1419A>G	p.Glu473=	synonymous_variant	11/48	5	NM_015295.3	P2
	ENST00000583546.1	n.371-8735T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 637 AN: 152208 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00495

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00401 AC: 982 AN: 245086 Hom.: 7 AF XY: 0.00418 AC XY: 556 AN XY: 132962

Gnomad AFR exome AF: 0.000527

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00234

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.00429

Gnomad OTH exome AF: 0.00502

GnomAD4 exome AF: 0.00461 AC: 6729 AN: 1459428 Hom.: 28 Cov.: 31 AF XY: 0.00461 AC XY: 3343 AN XY: 725920

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.00234

Gnomad4 ASJ exome AF: 0.00196

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00227

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.00494

Gnomad4 OTH exome AF: 0.00398

GnomAD4 genome AF: 0.00418 AC: 636 AN: 152326 Hom.: 2 Cov.: 32 AF XY: 0.00458 AC XY: 341 AN XY: 74488

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0170

Gnomad4 NFE AF: 0.00495

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00416 Hom.: 0

Bravo AF: 0.00328

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	SMCHD1: BP4, BP7, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 07, 2015	- -

Facioscapulohumeral muscular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

SMCHD1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.2
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs117771893; hg19: chr18-2700613; COSMIC: COSV55253403; COSMIC: COSV55253403;