rs9961682

Positions:

• chr18-2728561-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_015295.3(SMCHD1):​c.2878A>G​(p.Ile960Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00587 in 1,613,044 control chromosomes in the GnomAD database, including 475 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (244 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (231 hom.)
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0640

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMCHD1. . Gene score misZ 3.6318 (greater than the threshold 3.09). Trascript score misZ 3.965 (greater than threshold 3.09). GenCC has associacion of gene with facioscapulohumeral muscular dystrophy, arhinia, choanal atresia, and microphthalmia, hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0013088584).
• BP6: Variant 18-2728561-A-G is Benign according to our data. Variant chr18-2728561-A-G is described in ClinVar as [Benign]. Clinvar id is 260641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2728561-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.2878A>G	p.Ile960Val	missense_variant	23/48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.2878A>G	p.Ile960Val	missense_variant	23/48	5	NM_015295.3	ENSP00000326603.7

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4731 AN: 152112 Hom.: 243 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.00777 AC: 1929 AN: 248322 Hom.: 91 AF XY: 0.00606 AC XY: 816 AN XY: 134758

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000489

Gnomad OTH exome AF: 0.00514

GnomAD4 exome AF: 0.00324 AC: 4728 AN: 1460816 Hom.: 231 Cov.: 31 AF XY: 0.00281 AC XY: 2043 AN XY: 726690

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.00531

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.00696

GnomAD4 genome AF: 0.0311 AC: 4737 AN: 152228 Hom.: 244 Cov.: 32 AF XY: 0.0305 AC XY: 2270 AN XY: 74440

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.00577 Hom.: 68

Bravo AF: 0.0353

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.110 AC: 409

ESP6500EA AF: 0.000854 AC: 7

ExAC AF: 0.00944 AC: 1140

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Facioscapulohumeral muscular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.1
DANN	Benign	0.80
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.13
Sift	Benign	0.30	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.043
MPC		0.18
ClinPred		0.0011	T
GERP RS		-3.5
Varity_R		0.018
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs9961682; hg19: chr18-2728559;