14-69973493-G-C

Variant names:

• chr14-69973493-G-C
• rs227446
• NM_001034852.3:c.379-2222G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001034852.3(SMOC1):​c.379-2222G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0728 in 152,184 control chromosomes in the GnomAD database, including 456 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.073 (456 hom., cov: 32)
• Consequence: SMOC1 NM_001034852.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58
• Publications: 2 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, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMOC1	NM_001034852.3	c.379-2222G>C		intron_variant	Intron 3 of 11	ENST00000361956.8	NP_001030024.1
SMOC1	NM_001425244.1	c.379-2222G>C		intron_variant	Intron 3 of 11		NP_001412173.1
SMOC1	NM_001425245.1	c.379-2222G>C		intron_variant	Intron 3 of 11		NP_001412174.1
SMOC1	NM_022137.6	c.379-2222G>C		intron_variant	Intron 3 of 11		NP_071420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMOC1	ENST00000361956.8	c.379-2222G>C		intron_variant	Intron 3 of 11	1	NM_001034852.3	ENSP00000355110.4
SMOC1	ENST00000381280.4	c.379-2222G>C		intron_variant	Intron 3 of 11	1		ENSP00000370680.4
SMOC1	ENST00000553839.1	n.281-2222G>C		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0728 AC: 11064 AN: 152066 Hom.: 454 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0574

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.0792

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.0584

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0615

Gnomad OTH AF: 0.0805

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0728 AC: 11078 AN: 152184 Hom.: 456 Cov.: 32 AF XY: 0.0708 AC XY: 5269 AN XY: 74374

African (AFR) AF: 0.109 AC: 4543 AN: 41514

American (AMR) AF: 0.0574 AC: 878 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 144 AN: 3472

East Asian (EAS) AF: 0.0790 AC: 409 AN: 5180

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4822

European-Finnish (FIN) AF: 0.0584 AC: 618 AN: 10586

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0615 AC: 4185 AN: 68010

Other (OTH) AF: 0.0797 AC: 168 AN: 2108

Alfa AF: 0.0237 Hom.: 16

Bravo AF: 0.0759

Asia WGS AF: 0.0570 AC: 196 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.32
DANN	Benign	0.21
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs227446; hg19: chr14-70440210;