rs2304859

Variant names:

• chr18-2750479-A-G
• rs2304859
• NM_015295.3:c.4137A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015295.3(SMCHD1):​c.4137A>G​(p.Ala1379Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,603,420 control chromosomes in the GnomAD database, including 78,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6924 hom., cov: 31)
  • Exomes 𝑓: 0.31 (71276 hom.)
• Consequence: SMCHD1 NM_015295.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.324
• Publications: 15 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, ClinGen, Illumina
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 18-2750479-A-G is Benign according to our data. Variant chr18-2750479-A-G is described in ClinVar as Benign. ClinVar VariationId is 260648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.324 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.482 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	NM_015295.3	MANE Select	c.4137A>G	p.Ala1379Ala	synonymous	Exon 32 of 48	NP_056110.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	ENST00000320876.11	TSL:5 MANE Select	c.4137A>G	p.Ala1379Ala	synonymous	Exon 32 of 48	ENSP00000326603.7
	SMCHD1	ENST00000688342.1		c.4137A>G	p.Ala1379Ala	synonymous	Exon 32 of 47	ENSP00000508422.1
	SMCHD1	ENST00000577880.5	TSL:2	n.2550A>G		non_coding_transcript_exon	Exon 21 of 38	ENSP00000463049.1

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45156 AN: 151810 Hom.: 6908 Cov.: 31

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.303

GnomAD2 exomes AF: 0.345 AC: 82065 AN: 237782 AF XY: 0.343

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.476

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.505

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.306 AC: 444643 AN: 1451492 Hom.: 71276 Cov.: 33 AF XY: 0.309 AC XY: 223004 AN XY: 721618

African (AFR) AF: 0.258 AC: 8602 AN: 33300

American (AMR) AF: 0.461 AC: 19950 AN: 43298

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 8403 AN: 25854

East Asian (EAS) AF: 0.467 AC: 18428 AN: 39446

South Asian (SAS) AF: 0.443 AC: 37780 AN: 85306

European-Finnish (FIN) AF: 0.264 AC: 14027 AN: 53060

Middle Eastern (MID) AF: 0.269 AC: 1539 AN: 5730

European-Non Finnish (NFE) AF: 0.287 AC: 316766 AN: 1105462

Other (OTH) AF: 0.319 AC: 19148 AN: 60036

GnomAD4 genome AF: 0.298 AC: 45204 AN: 151928 Hom.: 6924 Cov.: 31 AF XY: 0.300 AC XY: 22262 AN XY: 74258

African (AFR) AF: 0.261 AC: 10838 AN: 41474

American (AMR) AF: 0.360 AC: 5481 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1101 AN: 3468

East Asian (EAS) AF: 0.498 AC: 2576 AN: 5170

South Asian (SAS) AF: 0.447 AC: 2154 AN: 4814

European-Finnish (FIN) AF: 0.266 AC: 2807 AN: 10562

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19112 AN: 67880

Other (OTH) AF: 0.306 AC: 645 AN: 2110

Alfa AF: 0.296 Hom.: 12209

Bravo AF: 0.307

Asia WGS AF: 0.491 AC: 1709 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.60
CADD	Benign	4.5
DANN	Benign	0.55
PhyloP100		0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2304859; hg19: chr18-2750477; COSMIC: COSV55253357; COSMIC: COSV55253357;