18-2750479-A-T

Variant names:

• chr18-2750479-A-T
• NM_015295.3:c.4137A>T
• SMCHD1 p.Ala1379Ala

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_015295.3(SMCHD1):​c.4137A>T​(p.Ala1379Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. A1379A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMCHD1 NM_015295.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.324
• 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: PanelApp Australia, Ambry Genetics, Illumina, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP7: Synonymous conserved (PhyloP=0.324 with no splicing effect.

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.4137A>T	p.Ala1379Ala	synonymous	Exon 32 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.4137A>T	p.Ala1379Ala	synonymous	Exon 32 of 48	ENSP00000326603.7	A6NHR9-1
	SMCHD1	ENST00000939310.1		c.4050A>T	p.Ala1350Ala	synonymous	Exon 32 of 48	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.4137A>T	p.Ala1379Ala	synonymous	Exon 32 of 47	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454036 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 722770

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 43416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 85398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107570

Other (OTH) AF: 0.00 AC: 0 AN: 60122

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.9
DANN	Benign	0.67
PhyloP100		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr18-2750477;