NM_015295.3:c.174G>C

Variant names:

• chr18-2656249-G-C
• rs2430853
• NM_015295.3:c.174G>C

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.174G>C​(p.Ala58Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,489,176 control chromosomes in the GnomAD database, including 241,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A58A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.63 (32063 hom., cov: 33)
  • Exomes 𝑓: 0.55 (208989 hom.)
• Consequence: SMCHD1 NM_015295.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.813
• 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: 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 18-2656249-G-C is Benign according to our data. Variant chr18-2656249-G-C is described in ClinVar as Benign. ClinVar VariationId is 260632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.813 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.842 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.174G>C	p.Ala58Ala	synonymous	Exon 1 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.174G>C	p.Ala58Ala	synonymous	Exon 1 of 48	ENSP00000326603.7	A6NHR9-1
	SMCHD1	ENST00000939310.1		c.174G>C	p.Ala58Ala	synonymous	Exon 1 of 48	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.174G>C	p.Ala58Ala	synonymous	Exon 1 of 47	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96332 AN: 152064 Hom.: 32011 Cov.: 33

Gnomad AFR AF: 0.849

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.672

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.631

GnomAD2 exomes AF: 0.558 AC: 82317 AN: 147528 AF XY: 0.557

Gnomad AFR exome AF: 0.851

Gnomad AMR exome AF: 0.539

Gnomad ASJ exome AF: 0.640

Gnomad EAS exome AF: 0.319

Gnomad FIN exome AF: 0.547

Gnomad NFE exome AF: 0.533

Gnomad OTH exome AF: 0.565

GnomAD4 exome AF: 0.555 AC: 741595 AN: 1336994 Hom.: 208989 Cov.: 46 AF XY: 0.557 AC XY: 368498 AN XY: 661722

African (AFR) AF: 0.873 AC: 22825 AN: 26160

American (AMR) AF: 0.554 AC: 11285 AN: 20366

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 14518 AN: 22162

East Asian (EAS) AF: 0.334 AC: 10580 AN: 31658

South Asian (SAS) AF: 0.631 AC: 43681 AN: 69266

European-Finnish (FIN) AF: 0.554 AC: 25862 AN: 46680

Middle Eastern (MID) AF: 0.674 AC: 3605 AN: 5348

European-Non Finnish (NFE) AF: 0.545 AC: 577686 AN: 1060444

Other (OTH) AF: 0.575 AC: 31553 AN: 54910

GnomAD4 genome AF: 0.634 AC: 96443 AN: 152182 Hom.: 32063 Cov.: 33 AF XY: 0.632 AC XY: 47043 AN XY: 74388

African (AFR) AF: 0.849 AC: 35286 AN: 41540

American (AMR) AF: 0.576 AC: 8810 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2275 AN: 3472

East Asian (EAS) AF: 0.342 AC: 1770 AN: 5172

South Asian (SAS) AF: 0.638 AC: 3080 AN: 4828

European-Finnish (FIN) AF: 0.570 AC: 6038 AN: 10588

Middle Eastern (MID) AF: 0.678 AC: 198 AN: 292

European-Non Finnish (NFE) AF: 0.545 AC: 37066 AN: 67972

Other (OTH) AF: 0.631 AC: 1332 AN: 2112

Alfa AF: 0.448 Hom.: 1129

Bravo AF: 0.642

Asia WGS AF: 0.520 AC: 1810 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Arrhinia with choanal atresia and microphthalmia syndrome (1)
-	-	1	Facioscapulohumeral muscular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.1
DANN	Benign	0.51
PhyloP100		-0.81
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
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: rs2430853; hg19: chr18-2656248; COSMIC: COSV55251101; COSMIC: COSV55251101;