rs76290319

Positions:

• chr18-2739450-T-A
• chr18-2739450-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_015295.3(SMCHD1):​c.3444T>A​(p.Pro1148=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,613,100 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: SMCHD1 NM_015295.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.360

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 18-2739450-T-A is Benign according to our data. Variant chr18-2739450-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196033.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr18-2739450-T-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.001 (153/152246) while in subpopulation NFE AF= 0.00171 (116/68006). AF 95% confidence interval is 0.00145. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 153 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.3444T>A	p.Pro1148=	synonymous_variant	27/48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.3444T>A	p.Pro1148=	synonymous_variant	27/48	5	NM_015295.3	ENSP00000326603	P2
	ENST00000583546.1	n.371-47570A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00105 AC: 261 AN: 248542 Hom.: 0 AF XY: 0.000979 AC XY: 132 AN XY: 134836

Gnomad AFR exome AF: 0.000453

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00135 AC: 1966 AN: 1460854 Hom.: 1 Cov.: 30 AF XY: 0.00131 AC XY: 953 AN XY: 726740

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000712

Gnomad4 NFE exome AF: 0.00159

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000967 AC XY: 72 AN XY: 74444

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.00100

Asia WGS AF: 0.000578 AC: 2 AN: 3474

EpiCase AF: 0.00120

EpiControl AF: 0.00184

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:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2021	This variant is associated with the following publications: (PMID: 25256356) -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.8
DANN	Benign	0.86

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: rs76290319; hg19: chr18-2739448;