rs7239096

Positions:

• chr18-2667006-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015295.3(SMCHD1):​c.399T>C​(p.Tyr133=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00615 in 1,593,436 control chromosomes in the GnomAD database, including 510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (264 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (246 hom.)
• Consequence: SMCHD1 NM_015295.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.60

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 18-2667006-T-C is Benign according to our data. Variant chr18-2667006-T-C is described in ClinVar as [Benign]. Clinvar id is 260646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2667006-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMCHD1	NM_015295.3	c.399T>C	p.Tyr133=	synonymous_variant	3/48	ENST00000320876.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCHD1	ENST00000320876.11	c.399T>C	p.Tyr133=	synonymous_variant	3/48	5	NM_015295.3	P2
SMCHD1	ENST00000688342.1	c.399T>C	p.Tyr133=	synonymous_variant	3/47			A2
SMCHD1	ENST00000684915.1	n.556T>C		non_coding_transcript_exon_variant	3/14

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4950 AN: 152192 Hom.: 263 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.00797 AC: 1724 AN: 216354 Hom.: 79 AF XY: 0.00611 AC XY: 713 AN XY: 116738

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.00495

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000255

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000486

Gnomad OTH exome AF: 0.00562

GnomAD4 exome AF: 0.00336 AC: 4845 AN: 1441126 Hom.: 246 Cov.: 30 AF XY: 0.00290 AC XY: 2075 AN XY: 715216

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.00552

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000334

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000220

Gnomad4 OTH exome AF: 0.00732

GnomAD4 genome AF: 0.0325 AC: 4957 AN: 152310 Hom.: 264 Cov.: 32 AF XY: 0.0321 AC XY: 2392 AN XY: 74486

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0138 Hom.: 56

Bravo AF: 0.0367

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Facioscapulohumeral muscular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.2
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs7239096; hg19: chr18-2667005;