NM_015295.3:c.386T>A

Variant names:

• chr18-2666993-T-A
• rs1135402738
• NM_015295.3:c.386T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_015295.3(SMCHD1):​c.386T>A​(p.Met129Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M129V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.56
• Publications: 2 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_015295.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-2666993-T-A is Pathogenic according to our data. Variant chr18-2666993-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 431462.Status of the report is no_assertion_criteria_provided, 0 stars.

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.386T>A	p.Met129Lys	missense	Exon 3 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.386T>A	p.Met129Lys	missense	Exon 3 of 48	ENSP00000326603.7
	SMCHD1	ENST00000939310.1		c.386T>A	p.Met129Lys	missense	Exon 3 of 48	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.386T>A	p.Met129Lys	missense	Exon 3 of 47	ENSP00000508422.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Arrhinia with choanal atresia and microphthalmia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.26
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.94	P
Vest4		0.92
MutPred		0.67		Gain of solvent accessibility (P = 0.012)
MVP		0.22
MPC		1.9
ClinPred		0.80	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.90
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs1135402738; hg19: chr18-2666992;