18-2656113-C-T

Variant names:

• chr18-2656113-C-T
• rs1417252379
• NM_015295.3:c.38C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015295.3(SMCHD1):​c.38C>T​(p.Ser13Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,458,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S13A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.837
• Publications: 0 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia, G2P
• 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

ENSG00000293256 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12972087).
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015295.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	NM_015295.3	MANE Select	c.38C>T	p.Ser13Phe	missense	Exon 1 of 48	NP_056110.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	ENST00000320876.11	TSL:5 MANE Select	c.38C>T	p.Ser13Phe	missense	Exon 1 of 48	ENSP00000326603.7	A6NHR9-1
	SMCHD1	ENST00000939310.1		c.38C>T	p.Ser13Phe	missense	Exon 1 of 48	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.38C>T	p.Ser13Phe	missense	Exon 1 of 47	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000168 AC: 22 AN: 1306588 Hom.: 0 Cov.: 29 AF XY: 0.0000171 AC XY: 11 AN XY: 644020

African (AFR) AF: 0.00 AC: 0 AN: 26098

American (AMR) AF: 0.00 AC: 0 AN: 19550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20018

East Asian (EAS) AF: 0.00 AC: 0 AN: 31026

South Asian (SAS) AF: 0.00 AC: 0 AN: 65090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5216

European-Non Finnish (NFE) AF: 0.0000202 AC: 21 AN: 1038066

Other (OTH) AF: 0.0000188 AC: 1 AN: 53152

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Facioscapulohumeral muscular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.84
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.13
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.025	D
Polyphen		0.16	B
Vest4		0.32
MutPred		0.36		Gain of sheet (P = 0.0085)
MVP		0.10
MPC		0.72
ClinPred		0.39	T
GERP RS		2.7
PromoterAI		0.055	Neutral
Varity_R		0.14
gMVP		0.26
Mutation Taster		=92/8	polymorphism

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: rs1417252379; hg19: chr18-2656112;