18-2771518-G-T

Variant names:

• chr18-2771518-G-T
• rs300291
• NM_015295.3:c.4967-15G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015295.3(SMCHD1):​c.4967-15G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,546,432 control chromosomes in the GnomAD database, including 768,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73791 hom., cov: 32)
  • Exomes 𝑓: 1.0 (694904 hom.)
• Consequence: SMCHD1 NM_015295.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.982
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 18-2771518-G-T is Benign according to our data. Variant chr18-2771518-G-T is described in CliVar as Benign. Clinvar id is 260652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2771518-G-T is described in CliVar as Benign. Clinvar id is 260652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2771518-G-T is described in CliVar as Benign. Clinvar id is 260652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2771518-G-T is described in CliVar as Benign. Clinvar id is 260652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2771518-G-T is described in CliVar as Benign. Clinvar id is 260652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.4967-15G>T		intron_variant	Intron 39 of 47	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.4967-15G>T		intron_variant	Intron 39 of 47	5	NM_015295.3	ENSP00000326603.7

Frequencies

GnomAD3 genomes AF: 0.984 AC: 149774 AN: 152206 Hom.: 73738 Cov.: 32

Gnomad AFR AF: 0.944

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.989

GnomAD2 exomes AF: 0.996 AC: 190726 AN: 191538 AF XY: 0.997

Gnomad AFR exome AF: 0.940

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.998 AC: 1391898 AN: 1394108 Hom.: 694904 Cov.: 26 AF XY: 0.999 AC XY: 692874 AN XY: 693846

African (AFR) AF: 0.941 AC: 26933 AN: 28628

American (AMR) AF: 0.997 AC: 25597 AN: 25686

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 23984 AN: 23984

East Asian (EAS) AF: 1.00 AC: 36026 AN: 36026

South Asian (SAS) AF: 1.00 AC: 74309 AN: 74318

European-Finnish (FIN) AF: 1.00 AC: 52818 AN: 52818

Middle Eastern (MID) AF: 0.995 AC: 5576 AN: 5606

European-Non Finnish (NFE) AF: 1.00 AC: 1089387 AN: 1089512

Other (OTH) AF: 0.995 AC: 57268 AN: 57530

GnomAD4 genome AF: 0.984 AC: 149886 AN: 152324 Hom.: 73791 Cov.: 32 AF XY: 0.984 AC XY: 73276 AN XY: 74484

African (AFR) AF: 0.945 AC: 39261 AN: 41568

American (AMR) AF: 0.994 AC: 15211 AN: 15304

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5190 AN: 5190

South Asian (SAS) AF: 1.00 AC: 4828 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10614 AN: 10614

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68014 AN: 68026

Other (OTH) AF: 0.989 AC: 2091 AN: 2114

Alfa AF: 0.977 Hom.: 22252

Bravo AF: 0.981

Asia WGS AF: 0.998 AC: 3452 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 09, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Facioscapulohumeral muscular dystrophy 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhinia with choanal atresia and microphthalmia syndrome Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.6
DANN	Benign	0.43
PhyloP100		0.98
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: rs300291; hg19: chr18-2771516;