rs8092725

Variant names:

• chr18-2738261-G-A
• rs8092725
• NM_015295.3:c.3277-136G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015295.3(SMCHD1):​c.3277-136G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 724,526 control chromosomes in the GnomAD database, including 17,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3115 hom., cov: 32)
  • Exomes 𝑓: 0.22 (14627 hom.)
• Consequence: SMCHD1 NM_015295.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.507
• Publications: 4 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, ClinGen, Illumina
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 18-2738261-G-A is Benign according to our data. Variant chr18-2738261-G-A is described in ClinVar as Benign. ClinVar VariationId is 1224606.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.3277-136G>A		intron_variant	Intron 25 of 47	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.3277-136G>A		intron_variant	Intron 25 of 47	5	NM_015295.3	ENSP00000326603.7

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29503 AN: 151922 Hom.: 3107 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.0768

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.202

GnomAD4 exome AF: 0.220 AC: 125788 AN: 572486 Hom.: 14627 AF XY: 0.221 AC XY: 64711 AN XY: 292984

African (AFR) AF: 0.121 AC: 1634 AN: 13486

American (AMR) AF: 0.291 AC: 3929 AN: 13522

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 2836 AN: 13254

East Asian (EAS) AF: 0.0753 AC: 2132 AN: 28324

South Asian (SAS) AF: 0.265 AC: 9974 AN: 37698

European-Finnish (FIN) AF: 0.225 AC: 6956 AN: 30936

Middle Eastern (MID) AF: 0.178 AC: 379 AN: 2132

European-Non Finnish (NFE) AF: 0.227 AC: 91713 AN: 404064

Other (OTH) AF: 0.214 AC: 6235 AN: 29070

GnomAD4 genome AF: 0.194 AC: 29524 AN: 152040 Hom.: 3115 Cov.: 32 AF XY: 0.196 AC XY: 14590 AN XY: 74310

African (AFR) AF: 0.117 AC: 4851 AN: 41456

American (AMR) AF: 0.257 AC: 3931 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 730 AN: 3468

East Asian (EAS) AF: 0.0772 AC: 400 AN: 5182

South Asian (SAS) AF: 0.269 AC: 1294 AN: 4814

European-Finnish (FIN) AF: 0.235 AC: 2488 AN: 10578

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14932 AN: 67952

Other (OTH) AF: 0.203 AC: 429 AN: 2112

Alfa AF: 0.217 Hom.: 6397

Bravo AF: 0.193

Asia WGS AF: 0.199 AC: 694 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 24, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	7.2
DANN	Benign	0.65
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8092725; hg19: chr18-2738259;