rs3213926

Variant names:

• chr18-2777925-A-G
• rs3213926
• NM_015295.3:c.5476+10A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015295.3(SMCHD1):​c.5476+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,465,200 control chromosomes in the GnomAD database, including 69,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6737 hom., cov: 33)
  • Exomes 𝑓: 0.30 (62728 hom.)
• Consequence: SMCHD1 NM_015295.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.337
• Publications: 9 publications found

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]

SMCHD1 Gene-Disease associations (from GenCC):

• arhinia, choanal atresia, and microphthalmia

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia, G2P
• facioscapulohumeral muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000266049 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-2777925-A-G is Benign according to our data. Variant chr18-2777925-A-G is described in ClinVar as Benign. ClinVar VariationId is 260654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.492 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015295.3. 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
	SMCHD1	NM_015295.3	MANE Select	c.5476+10A>G		intron	N/A	NP_056110.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	ENST00000320876.11	TSL:5 MANE Select	c.5476+10A>G		intron	N/A	ENSP00000326603.7	A6NHR9-1
	SMCHD1	ENST00000939310.1		c.5389+10A>G		intron	N/A	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.5344+10A>G		intron	N/A	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44402 AN: 151986 Hom.: 6725 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.299

GnomAD2 exomes AF: 0.344 AC: 48452 AN: 140654 AF XY: 0.346

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.525

Gnomad FIN exome AF: 0.268

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.320

GnomAD4 exome AF: 0.303 AC: 397439 AN: 1313096 Hom.: 62728 Cov.: 20 AF XY: 0.305 AC XY: 198031 AN XY: 648844

African (AFR) AF: 0.240 AC: 6985 AN: 29132

American (AMR) AF: 0.440 AC: 13121 AN: 29840

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 7699 AN: 23734

East Asian (EAS) AF: 0.470 AC: 16493 AN: 35110

South Asian (SAS) AF: 0.424 AC: 30215 AN: 71272

European-Finnish (FIN) AF: 0.265 AC: 12867 AN: 48600

Middle Eastern (MID) AF: 0.266 AC: 1448 AN: 5444

European-Non Finnish (NFE) AF: 0.287 AC: 291042 AN: 1015046

Other (OTH) AF: 0.320 AC: 17569 AN: 54918

GnomAD4 genome AF: 0.292 AC: 44442 AN: 152104 Hom.: 6737 Cov.: 33 AF XY: 0.294 AC XY: 21851 AN XY: 74352

African (AFR) AF: 0.244 AC: 10118 AN: 41524

American (AMR) AF: 0.359 AC: 5483 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1098 AN: 3470

East Asian (EAS) AF: 0.508 AC: 2629 AN: 5174

South Asian (SAS) AF: 0.431 AC: 2075 AN: 4818

European-Finnish (FIN) AF: 0.265 AC: 2802 AN: 10558

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19111 AN: 67970

Other (OTH) AF: 0.302 AC: 637 AN: 2112

Alfa AF: 0.285 Hom.: 2094

Bravo AF: 0.302

Asia WGS AF: 0.487 AC: 1689 AN: 3466

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Arrhinia with choanal atresia and microphthalmia syndrome (1)
-	-	1	Facioscapulohumeral muscular dystrophy 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.8
DANN	Benign	0.33
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3213926; hg19: chr18-2777923;