rs76290319

Variant names:

• chr18-2739450-T-A
• rs76290319
• NM_015295.3:c.3444T>A

Your query was ambiguous. Multiple possible variants found:

• chr18-2739450-T-A
• chr18-2739450-T-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_015295.3(SMCHD1):​c.3444T>A​(p.Pro1148Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,613,100 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: SMCHD1 NM_015295.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.360
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 18-2739450-T-A is Benign according to our data. Variant chr18-2739450-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196033.
• BP7: Synonymous conserved (PhyloP=0.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.001 (153/152246) while in subpopulation NFE AF = 0.00171 (116/68006). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 153 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	NM_015295.3	MANE Select	c.3444T>A	p.Pro1148Pro	synonymous	Exon 27 of 48	NP_056110.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	ENST00000320876.11	TSL:5 MANE Select	c.3444T>A	p.Pro1148Pro	synonymous	Exon 27 of 48	ENSP00000326603.7
	SMCHD1	ENST00000688342.1		c.3444T>A	p.Pro1148Pro	synonymous	Exon 27 of 47	ENSP00000508422.1
	SMCHD1	ENST00000577880.5	TSL:2	n.1857T>A		non_coding_transcript_exon	Exon 16 of 38	ENSP00000463049.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00105 AC: 261 AN: 248542 AF XY: 0.000979

Gnomad AFR exome AF: 0.000453

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00135 AC: 1966 AN: 1460854 Hom.: 1 Cov.: 30 AF XY: 0.00131 AC XY: 953 AN XY: 726740

African (AFR) AF: 0.000299 AC: 10 AN: 33416

American (AMR) AF: 0.00157 AC: 70 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.000712 AC: 38 AN: 53394

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.00159 AC: 1767 AN: 1111394

Other (OTH) AF: 0.00131 AC: 79 AN: 60324

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000967 AC XY: 72 AN XY: 74444

African (AFR) AF: 0.000313 AC: 13 AN: 41542

American (AMR) AF: 0.00131 AC: 20 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00171 AC: 116 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.00100

Asia WGS AF: 0.000578 AC: 2 AN: 3474

EpiCase AF: 0.00120

EpiControl AF: 0.00184

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Facioscapulohumeral muscular dystrophy 2 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.8
DANN	Benign	0.86
PhyloP100		0.36
Mutation Taster		=100/0	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: rs76290319; hg19: chr18-2739448;