Genetic Variant SMCHD1:p.Phe1565Phe (chr18-2763765-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_015295.3(SMCHD1):c.4695C>T(p.Phe1565Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,456,300 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SMCHD1
NM_015295.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.75

Publications

0 publications found

Variant links:

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

SMCHD1 links:

ENSG00000266049 (HGNC:):

ENSG00000266049 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 18-2763765-C-T is Benign according to our data. Variant chr18-2763765-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260651.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BP7

Synonymous conserved (PhyloP=1.75 with no splicing effect.

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3 link	c.4695C>T	p.Phe1565Phe	synonymous_variant	Exon 37 of 48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11 link	c.4695C>T	p.Phe1565Phe	synonymous_variant	Exon 37 of 48	5	NM_015295.3	ENSP00000326603.7		A6NHR9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000412

AC:

AN:

242490

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000618

AC:

AN:

1456300

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724422

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33022

American (AMR)

AF:

0.00

AC:

AN:

43484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39430

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00000541

AC:

AN:

1109884

Other (OTH)

AF:

0.0000166

AC:

AN:

60156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Aug 15, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely 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

-0.35

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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18-2763765-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over