rs770327555

Variant names:

• chr14-69879739-C-A
• rs770327555
• NM_001034852.3:c.61C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-69879739-C-A
• chr14-69879739-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001034852.3(SMOC1):​c.61C>A​(p.Leu21Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L21L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMOC1 NM_001034852.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 0 publications found

Genes affected

SMOC1 (HGNC:20318): (SPARC related modular calcium binding 1) This gene encodes a multi-domain secreted protein that may have a critical role in ocular and limb development. Mutations in this gene are associated with microphthalmia and limb anomalies. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

SMOC1 Gene-Disease associations (from GenCC):

• microphthalmia with limb anomalies

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16878033).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034852.3. 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
	SMOC1	NM_001034852.3	MANE Select	c.61C>A	p.Leu21Met	missense	Exon 1 of 12	NP_001030024.1	Q9H4F8-2
	SMOC1	NM_001425244.1		c.61C>A	p.Leu21Met	missense	Exon 1 of 12	NP_001412173.1
	SMOC1	NM_001425245.1		c.61C>A	p.Leu21Met	missense	Exon 1 of 12	NP_001412174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMOC1	ENST00000361956.8	TSL:1 MANE Select	c.61C>A	p.Leu21Met	missense	Exon 1 of 12	ENSP00000355110.4	Q9H4F8-2
	SMOC1	ENST00000381280.4	TSL:1	c.61C>A	p.Leu21Met	missense	Exon 1 of 12	ENSP00000370680.4	Q9H4F8-1
	SMOC1	ENST00000853906.1		c.61C>A	p.Leu21Met	missense	Exon 1 of 13	ENSP00000523965.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440618 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716570

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33088

American (AMR) AF: 0.0000228 AC: 1 AN: 43820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 38978

South Asian (SAS) AF: 0.00 AC: 0 AN: 84416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108534

Other (OTH) AF: 0.00 AC: 0 AN: 59920

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.049
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.021	D
Polyphen		0.49	P
Vest4		0.33
MutPred		0.41		Gain of catalytic residue at L21 (P = 0.103)
MVP		0.47
MPC		0.94
ClinPred		0.45	T
GERP RS		2.2
PromoterAI		0.022	Neutral
Varity_R		0.19
gMVP		0.13
Mutation Taster		=85/15	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: rs770327555; hg19: chr14-70346456;