rs113524119

Positions:

• chr18-2707800-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015295.3(SMCHD1):​c.2147-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,586,846 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (31 hom.)
• Consequence: SMCHD1 NM_015295.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004144
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00400

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 18-2707800-C-T is Benign according to our data. Variant chr18-2707800-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 260638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2707800-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00455 (692/152124) while in subpopulation NFE AF= 0.00557 (379/68014). AF 95% confidence interval is 0.00511. There are 5 homozygotes in gnomad4. There are 377 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 692 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.2147-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.2147-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_015295.3	ENSP00000326603	P2
	ENST00000583546.1	n.371-15920G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 692 AN: 152006 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00557

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00491 AC: 1085 AN: 221190 Hom.: 6 AF XY: 0.00479 AC XY: 577 AN XY: 120458

Gnomad AFR exome AF: 0.000706

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.000232

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.0200

Gnomad NFE exome AF: 0.00569

Gnomad OTH exome AF: 0.00412

GnomAD4 exome AF: 0.00456 AC: 6540 AN: 1434722 Hom.: 31 Cov.: 29 AF XY: 0.00447 AC XY: 3190 AN XY: 713344

Gnomad4 AFR exome AF: 0.000722

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.000120

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000559

Gnomad4 FIN exome AF: 0.0196

Gnomad4 NFE exome AF: 0.00468

Gnomad4 OTH exome AF: 0.00356

GnomAD4 genome AF: 0.00455 AC: 692 AN: 152124 Hom.: 5 Cov.: 32 AF XY: 0.00507 AC XY: 377 AN XY: 74366

Gnomad4 AFR AF: 0.000675

Gnomad4 AMR AF: 0.00295

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0214

Gnomad4 NFE AF: 0.00557

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00469 Hom.: 4

Bravo AF: 0.00289

Asia WGS AF: 0.000868 AC: 3 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2021	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SMCHD1: BP4, BS2 -

Facioscapulohumeral muscular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.8
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.036
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: rs113524119; hg19: chr18-2707798;