rs1057519641

Positions:

• chr18-2667030-G-A
• chr18-2667030-G-C
• chr18-2667030-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_015295.3(SMCHD1):​c.423G>A​(p.Leu141Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,416,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMCHD1 NM_015295.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004958
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP7: Synonymous conserved (PhyloP=2.03 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.423G>A	p.Leu141Leu	splice_region_variant, synonymous_variant	3/48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.423G>A	p.Leu141Leu	splice_region_variant, synonymous_variant	3/48	5	NM_015295.3	ENSP00000326603.7
SMCHD1	ENST00000688342.1	c.423G>A	p.Leu141Leu	splice_region_variant, synonymous_variant	3/47			ENSP00000508422.1
SMCHD1	ENST00000684915.1	n.580G>A		splice_region_variant, non_coding_transcript_exon_variant	3/14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000542 AC: 1 AN: 184448 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 98454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000375

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1416910 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 700936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000262

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	13
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00050
dbscSNV1_RF	Benign	0.064
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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519641; hg19: chr18-2667029;