18-2763699-C-T

Variant names:

• chr18-2763699-C-T
• rs483547
• NM_015295.3:c.4629C>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.4629C>T​(p.Gly1543Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,605,584 control chromosomes in the GnomAD database, including 142,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11751 hom., cov: 32)
  • Exomes 𝑓: 0.42 (130630 hom.)
• Consequence: SMCHD1 NM_015295.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.850
• Publications: 20 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=-0.57).
• BP6: Variant 18-2763699-C-T is Benign according to our data. Variant chr18-2763699-C-T is described in ClinVar as Benign. ClinVar VariationId is 260650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.85 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.446 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.4629C>T	p.Gly1543Gly	synonymous	Exon 37 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.4629C>T	p.Gly1543Gly	synonymous	Exon 37 of 48	ENSP00000326603.7
	SMCHD1	ENST00000939310.1		c.4542C>T	p.Gly1514Gly	synonymous	Exon 37 of 48	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.4497C>T	p.Gly1499Gly	synonymous	Exon 36 of 47	ENSP00000508422.1

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58294 AN: 151866 Hom.: 11749 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.366

GnomAD2 exomes AF: 0.361 AC: 87017 AN: 241252 AF XY: 0.360

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.308

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.481

Gnomad NFE exome AF: 0.444

Gnomad OTH exome AF: 0.381

GnomAD4 exome AF: 0.415 AC: 603963 AN: 1453600 Hom.: 130630 Cov.: 32 AF XY: 0.409 AC XY: 296003 AN XY: 723192

African (AFR) AF: 0.289 AC: 9482 AN: 32860

American (AMR) AF: 0.317 AC: 13721 AN: 43314

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 7833 AN: 25996

East Asian (EAS) AF: 0.208 AC: 8161 AN: 39234

South Asian (SAS) AF: 0.199 AC: 16986 AN: 85310

European-Finnish (FIN) AF: 0.479 AC: 25533 AN: 53300

Middle Eastern (MID) AF: 0.315 AC: 1809 AN: 5750

European-Non Finnish (NFE) AF: 0.449 AC: 497459 AN: 1107810

Other (OTH) AF: 0.383 AC: 22979 AN: 60026

GnomAD4 genome AF: 0.384 AC: 58317 AN: 151984 Hom.: 11751 Cov.: 32 AF XY: 0.381 AC XY: 28325 AN XY: 74294

African (AFR) AF: 0.303 AC: 12570 AN: 41462

American (AMR) AF: 0.392 AC: 5991 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1111 AN: 3470

East Asian (EAS) AF: 0.187 AC: 971 AN: 5182

South Asian (SAS) AF: 0.190 AC: 915 AN: 4816

European-Finnish (FIN) AF: 0.476 AC: 5008 AN: 10530

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.451 AC: 30595 AN: 67910

Other (OTH) AF: 0.364 AC: 769 AN: 2112

Alfa AF: 0.391 Hom.: 6226

Bravo AF: 0.370

Asia WGS AF: 0.179 AC: 624 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Facioscapulohumeral muscular dystrophy 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.2
DANN	Benign	0.73
PhyloP100		0.85
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: rs483547; hg19: chr18-2763697; COSMIC: COSV55257520;