rs372945746

Variant names:

• chr18-2707811-G-A
• rs372945746
• NM_015295.3:c.2151G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-2707811-G-A
• chr18-2707811-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_015295.3(SMCHD1):​c.2151G>A​(p.Ala717Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,600,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: SMCHD1 NM_015295.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.276
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 18-2707811-G-A is Benign according to our data. Variant chr18-2707811-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 498203.
• BP7: Synonymous conserved (PhyloP=0.276 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000348 (53/152226) while in subpopulation AFR AF = 0.0012 (50/41522). AF 95% confidence interval is 0.000938. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 53 AD gene.

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.2151G>A	p.Ala717Ala	synonymous	Exon 17 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.2151G>A	p.Ala717Ala	synonymous	Exon 17 of 48	ENSP00000326603.7
	SMCHD1	ENST00000939310.1		c.2064G>A	p.Ala688Ala	synonymous	Exon 17 of 48	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.2151G>A	p.Ala717Ala	synonymous	Exon 17 of 47	ENSP00000508422.1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152108 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000107 AC: 25 AN: 232942 AF XY: 0.0000869

Gnomad AFR exome AF: 0.000971

Gnomad AMR exome AF: 0.000191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000947

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000511 AC: 74 AN: 1448496 Hom.: 0 Cov.: 30 AF XY: 0.0000528 AC XY: 38 AN XY: 720220

African (AFR) AF: 0.000978 AC: 32 AN: 32732

American (AMR) AF: 0.000143 AC: 6 AN: 41896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25584

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.000107 AC: 9 AN: 84358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53078

Middle Eastern (MID) AF: 0.000192 AC: 1 AN: 5196

European-Non Finnish (NFE) AF: 0.0000163 AC: 18 AN: 1106312

Other (OTH) AF: 0.000134 AC: 8 AN: 59810

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152226 Hom.: 0 Cov.: 31 AF XY: 0.000255 AC XY: 19 AN XY: 74426

African (AFR) AF: 0.00120 AC: 50 AN: 41522

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000313 Hom.: 0

Bravo AF: 0.000559

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.6
DANN	Benign	0.56
PhyloP100		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs372945746; hg19: chr18-2707809;