rs1057519643

Variant names:

• chr18-2667015-A-C
• rs1057519643
• NM_015295.3:c.408A>C

Your query was ambiguous. Multiple possible variants found:

• chr18-2667015-A-C
• chr18-2667015-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_015295.3(SMCHD1):​c.408A>C​(p.Glu136Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E136E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 4.00
• Publications: 2 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_015295.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-2667015-A-C is Pathogenic according to our data. Variant chr18-2667015-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 375764.

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.408A>C	p.Glu136Asp	missense	Exon 3 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.408A>C	p.Glu136Asp	missense	Exon 3 of 48	ENSP00000326603.7	A6NHR9-1
	SMCHD1	ENST00000939310.1		c.408A>C	p.Glu136Asp	missense	Exon 3 of 48	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.408A>C	p.Glu136Asp	missense	Exon 3 of 47	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	Arrhinia with choanal atresia and microphthalmia syndrome (3)
1	1	-	Facioscapulohumeral muscular dystrophy 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.17	T
Sift4G	Benign	0.061	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.24		Gain of sheet (P = 0.0266)
MVP		0.28
MPC		1.6
ClinPred		0.93	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.71
Mutation Taster		=58/42	disease causing (ClinVar)

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: rs1057519643; hg19: chr18-2667014;