rs144115061

Variant names:

• chr18-2796115-T-G
• rs144115061
• NM_015295.3:c.5878+8T>G

Your query was ambiguous. Multiple possible variants found:

• chr18-2796115-T-G
• chr18-2796115-T-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015295.3(SMCHD1):​c.5878+8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,523,842 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: SMCHD1 NM_015295.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003474
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.622
• 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: 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

ENSG00000266049 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 18-2796115-T-G is Benign according to our data. Variant chr18-2796115-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260656.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000958 (146/152352) while in subpopulation AMR AF = 0.00229 (35/15292). AF 95% confidence interval is 0.00169. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 146 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.5878+8T>G		splice_region intron	N/A	NP_056110.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	ENST00000320876.11	TSL:5 MANE Select	c.5878+8T>G		splice_region intron	N/A	ENSP00000326603.7	A6NHR9-1
	SMCHD1	ENST00000939310.1		c.5791+8T>G		splice_region intron	N/A	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.5746+8T>G		splice_region intron	N/A	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000764 AC: 99 AN: 129540 AF XY: 0.000745

Gnomad AFR exome AF: 0.000234

Gnomad AMR exome AF: 0.00141

Gnomad ASJ exome AF: 0.000168

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000675

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.00138 AC: 1894 AN: 1371490 Hom.: 2 Cov.: 29 AF XY: 0.00134 AC XY: 905 AN XY: 676830

African (AFR) AF: 0.000466 AC: 14 AN: 30014

American (AMR) AF: 0.00157 AC: 41 AN: 26134

Ashkenazi Jewish (ASJ) AF: 0.0000433 AC: 1 AN: 23074

East Asian (EAS) AF: 0.00 AC: 0 AN: 36692

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73562

European-Finnish (FIN) AF: 0.0000408 AC: 2 AN: 49044

Middle Eastern (MID) AF: 0.000369 AC: 2 AN: 5422

European-Non Finnish (NFE) AF: 0.00162 AC: 1735 AN: 1070864

Other (OTH) AF: 0.00173 AC: 98 AN: 56684

GnomAD4 genome AF: 0.000958 AC: 146 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000711 AC XY: 53 AN XY: 74510

African (AFR) AF: 0.000192 AC: 8 AN: 41592

American (AMR) AF: 0.00229 AC: 35 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000994

ClinVar

ClinVar submissions

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.9
DANN	Benign	0.44
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.0
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: rs144115061; hg19: chr18-2796113;