18-2707811-G-T

Variant names:

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

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.2151G>T​(p.Ala717Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A717A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SMCHD1 NM_015295.3 synonymous
• Clinical Significance: Not reported in ClinVar
• 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: 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=-0.47).
• BP7: Synonymous conserved (PhyloP=0.276 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.2151G>T	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>T	p.Ala717Ala	synonymous	Exon 17 of 48	ENSP00000326603.7
	SMCHD1	ENST00000939310.1		c.2064G>T	p.Ala688Ala	synonymous	Exon 17 of 48	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.2151G>T	p.Ala717Ala	synonymous	Exon 17 of 47	ENSP00000508422.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448498 Hom.: 0 Cov.: 30 AF XY: 0.00000417 AC XY: 3 AN XY: 720222

African (AFR) AF: 0.00 AC: 0 AN: 32732

American (AMR) AF: 0.00 AC: 0 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: 0.0000119 AC: 1 AN: 84358

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5196

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106314

Other (OTH) AF: 0.0000334 AC: 2 AN: 59810

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.60
DANN	Benign	0.65
PhyloP100		0.28

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;