NM_015295.3:c.3528A>G

Variant names:

• chr18-2740716-A-G
• rs12327477
• NM_015295.3:c.3528A>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.3528A>G​(p.Thr1176Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,577,326 control chromosomes in the GnomAD database, including 76,454 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6927 hom., cov: 32)
  • Exomes 𝑓: 0.30 (69527 hom.)
• Consequence: SMCHD1 NM_015295.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.857
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 18-2740716-A-G is Benign according to our data. Variant chr18-2740716-A-G is described in ClinVar as Benign. ClinVar VariationId is 260643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.857 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.48 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.3528A>G	p.Thr1176Thr	synonymous	Exon 28 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.3528A>G	p.Thr1176Thr	synonymous	Exon 28 of 48	ENSP00000326603.7	A6NHR9-1
	SMCHD1	ENST00000939310.1		c.3441A>G	p.Thr1147Thr	synonymous	Exon 28 of 48	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.3528A>G	p.Thr1176Thr	synonymous	Exon 28 of 47	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45168 AN: 151840 Hom.: 6911 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.496

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.304

GnomAD2 exomes AF: 0.343 AC: 82694 AN: 241024 AF XY: 0.340

Gnomad AFR exome AF: 0.267

Gnomad AMR exome AF: 0.476

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.506

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.305 AC: 434133 AN: 1425368 Hom.: 69527 Cov.: 26 AF XY: 0.307 AC XY: 217985 AN XY: 709618

African (AFR) AF: 0.257 AC: 8367 AN: 32594

American (AMR) AF: 0.460 AC: 19608 AN: 42584

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 8274 AN: 25556

East Asian (EAS) AF: 0.465 AC: 18194 AN: 39104

South Asian (SAS) AF: 0.441 AC: 35811 AN: 81194

European-Finnish (FIN) AF: 0.265 AC: 13964 AN: 52786

Middle Eastern (MID) AF: 0.267 AC: 1491 AN: 5582

European-Non Finnish (NFE) AF: 0.285 AC: 309663 AN: 1086924

Other (OTH) AF: 0.318 AC: 18761 AN: 59044

GnomAD4 genome AF: 0.298 AC: 45216 AN: 151958 Hom.: 6927 Cov.: 32 AF XY: 0.300 AC XY: 22249 AN XY: 74272

African (AFR) AF: 0.261 AC: 10832 AN: 41454

American (AMR) AF: 0.359 AC: 5481 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1100 AN: 3470

East Asian (EAS) AF: 0.496 AC: 2564 AN: 5168

South Asian (SAS) AF: 0.447 AC: 2157 AN: 4822

European-Finnish (FIN) AF: 0.266 AC: 2805 AN: 10554

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

European-Non Finnish (NFE) AF: 0.282 AC: 19143 AN: 67930

Other (OTH) AF: 0.307 AC: 646 AN: 2106

Alfa AF: 0.288 Hom.: 5025

Bravo AF: 0.307

Asia WGS AF: 0.491 AC: 1696 AN: 3452

ClinVar

ClinVar submissions

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	-0.57
CADD	Benign	4.5
DANN	Benign	0.75
PhyloP100		0.86
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: rs12327477; hg19: chr18-2740714; COSMIC: COSV55252845; COSMIC: COSV55252845;