chr18-2656103-G-GGTGGGGCCTCT

Variant names:

• chr18-2656103-G-GGTGGGGCCTCT
• rs2143729488
• NM_015295.3:c.35_45dupCCTCTGTGGGG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_015295.3(SMCHD1):​c.35_45dupCCTCTGTGGGG​(p.Thr16ProfsTer97) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMCHD1 NM_015295.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.760
• Publications: 1 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

ENSG00000293256 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 102 pathogenic variants in the truncated region.
• PP5: Variant 18-2656103-G-GGTGGGGCCTCT is Pathogenic according to our data. Variant chr18-2656103-G-GGTGGGGCCTCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2433595.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.35_45dupCCTCTGTGGGG	p.Thr16ProfsTer97	frameshift_variant	Exon 1 of 48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.35_45dupCCTCTGTGGGG	p.Thr16ProfsTer97	frameshift_variant	Exon 1 of 48	5	NM_015295.3	ENSP00000326603.7
SMCHD1	ENST00000688342.1	c.35_45dupCCTCTGTGGGG	p.Thr16ProfsTer97	frameshift_variant	Exon 1 of 47			ENSP00000508422.1
SMCHD1	ENST00000684915.1	n.192_202dupCCTCTGTGGGG		non_coding_transcript_exon_variant	Exon 1 of 14
ENSG00000293256	ENST00000733457.1	n.-244_-234dupAGAGGCCCCAC		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 16, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.76

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2143729488; hg19: chr18-2656102;