rs201069969

chr18-2706361-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015295.3(SMCHD1):c.1957-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,540,260 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 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 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (4 hom.)
• Consequence: SMCHD1 NM_015295.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002092
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.637

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 18-2706361-C-T is Benign according to our data. Variant chr18-2706361-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260635.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2, Uncertain_significance=1}. Variant chr18-2706361-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000519 (79/152174) while in subpopulation SAS AF= 0.00477 (23/4824). AF 95% confidence interval is 0.00326. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMCHD1	NM_015295.3	c.1957-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000320876.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCHD1	ENST00000320876.11	c.1957-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_015295.3	P2
	ENST00000583546.1	n.371-14481G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000520 AC: 79 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000795 AC: 140 AN: 176008 Hom.: 2 AF XY: 0.000932 AC XY: 87 AN XY: 93392

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000765

Gnomad SAS exome AF: 0.00377

Gnomad FIN exome AF: 0.000110

Gnomad NFE exome AF: 0.000579

Gnomad OTH exome AF: 0.000434

GnomAD4 exome AF: 0.000732 AC: 1016 AN: 1388086 Hom.: 4 Cov.: 26 AF XY: 0.000824 AC XY: 565 AN XY: 685266

Gnomad4 AFR exome AF: 0.000286

Gnomad4 AMR exome AF: 0.000370

Gnomad4 ASJ exome AF: 0.0000408

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00424

Gnomad4 FIN exome AF: 0.0000995

Gnomad4 NFE exome AF: 0.000581

Gnomad4 OTH exome AF: 0.000608

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74400

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.000677

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000467 Hom.: 0

Bravo AF: 0.000340

Asia WGS AF: 0.000289 AC: 3 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Facioscapulohumeral muscular dystrophy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	10
Dann	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.030		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: rs201069969; hg19: chr18-2706359;