rs635132

Variant names:

• chr18-2705702-A-G
• rs635132
• NM_015295.3:c.1851A>G

Your query was ambiguous. Multiple possible variants found:

• chr18-2705702-A-G
• chr18-2705702-A-T

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.1851A>G​(p.Thr617Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 1,550,818 control chromosomes in the GnomAD database, including 389,900 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (30718 hom., cov: 28)
  • Exomes 𝑓: 0.71 (359182 hom.)
• Consequence: SMCHD1 NM_015295.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.334
• Publications: 17 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: Illumina, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
• 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=-0.51).
• BP6: Variant 18-2705702-A-G is Benign according to our data. Variant chr18-2705702-A-G is described in ClinVar as Benign. ClinVar VariationId is 260633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.334 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.723 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.1851A>G	p.Thr617Thr	synonymous	Exon 14 of 48	NP_056110.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	ENST00000320876.11	TSL:5 MANE Select	c.1851A>G	p.Thr617Thr	synonymous	Exon 14 of 48	ENSP00000326603.7	A6NHR9-1
	SMCHD1	ENST00000939310.1		c.1764A>G	p.Thr588Thr	synonymous	Exon 14 of 48	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.1851A>G	p.Thr617Thr	synonymous	Exon 14 of 47	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes AF: 0.612 AC: 92435 AN: 150978 Hom.: 30704 Cov.: 28

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.672

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.753

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.610

GnomAD2 exomes AF: 0.694 AC: 167030 AN: 240620 AF XY: 0.695

Gnomad AFR exome AF: 0.328

Gnomad AMR exome AF: 0.777

Gnomad ASJ exome AF: 0.653

Gnomad EAS exome AF: 0.673

Gnomad FIN exome AF: 0.758

Gnomad NFE exome AF: 0.726

Gnomad OTH exome AF: 0.694

GnomAD4 exome AF: 0.712 AC: 996360 AN: 1399724 Hom.: 359182 Cov.: 21 AF XY: 0.710 AC XY: 496261 AN XY: 699028

African (AFR) AF: 0.309 AC: 10044 AN: 32500

American (AMR) AF: 0.768 AC: 33229 AN: 43270

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 16274 AN: 25334

East Asian (EAS) AF: 0.674 AC: 26276 AN: 38980

South Asian (SAS) AF: 0.649 AC: 53146 AN: 81898

European-Finnish (FIN) AF: 0.751 AC: 39101 AN: 52040

Middle Eastern (MID) AF: 0.565 AC: 3159 AN: 5590

European-Non Finnish (NFE) AF: 0.730 AC: 775637 AN: 1062116

Other (OTH) AF: 0.681 AC: 39494 AN: 57996

GnomAD4 genome AF: 0.612 AC: 92474 AN: 151094 Hom.: 30718 Cov.: 28 AF XY: 0.615 AC XY: 45350 AN XY: 73798

African (AFR) AF: 0.331 AC: 13644 AN: 41256

American (AMR) AF: 0.718 AC: 10883 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2278 AN: 3470

East Asian (EAS) AF: 0.680 AC: 3506 AN: 5154

South Asian (SAS) AF: 0.644 AC: 3092 AN: 4802

European-Finnish (FIN) AF: 0.753 AC: 7674 AN: 10196

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.728 AC: 49353 AN: 67756

Other (OTH) AF: 0.612 AC: 1280 AN: 2092

Alfa AF: 0.683 Hom.: 86533

Bravo AF: 0.599

Asia WGS AF: 0.663 AC: 2301 AN: 3472

ClinVar

ClinVar submissions as Germline

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	-0.51
CADD	Benign	6.6
DANN	Benign	0.70
PhyloP100		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs635132; hg19: chr18-2705700; COSMIC: COSV108017404; COSMIC: COSV108017404;