rs138862255

Variant names:

• chr14-69879699-C-T
• rs138862255
• NM_001034852.3:c.21C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001034852.3(SMOC1):​c.21C>T​(p.Ala7Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,578,372 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: SMOC1 NM_001034852.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.379
• Publications: 1 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 14-69879699-C-T is Benign according to our data. Variant chr14-69879699-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 778483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.379 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00125 (190/152306) while in subpopulation NFE AF = 0.00181 (123/68002). AF 95% confidence interval is 0.00155. There are 0 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.21C>T	p.Ala7Ala	synonymous	Exon 1 of 12	NP_001030024.1	Q9H4F8-2
	SMOC1	NM_001425244.1		c.21C>T	p.Ala7Ala	synonymous	Exon 1 of 12	NP_001412173.1
	SMOC1	NM_001425245.1		c.21C>T	p.Ala7Ala	synonymous	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.21C>T	p.Ala7Ala	synonymous	Exon 1 of 12	ENSP00000355110.4	Q9H4F8-2
	SMOC1	ENST00000381280.4	TSL:1	c.21C>T	p.Ala7Ala	synonymous	Exon 1 of 12	ENSP00000370680.4	Q9H4F8-1
	SMOC1	ENST00000853906.1		c.21C>T	p.Ala7Ala	synonymous	Exon 1 of 13	ENSP00000523965.1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00123 AC: 238 AN: 193996 AF XY: 0.00118

Gnomad AFR exome AF: 0.000191

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00303

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00162

GnomAD4 exome AF: 0.00174 AC: 2478 AN: 1426066 Hom.: 3 Cov.: 31 AF XY: 0.00166 AC XY: 1178 AN XY: 708748

African (AFR) AF: 0.000156 AC: 5 AN: 32032

American (AMR) AF: 0.000236 AC: 10 AN: 42320

Ashkenazi Jewish (ASJ) AF: 0.00297 AC: 76 AN: 25594

East Asian (EAS) AF: 0.00 AC: 0 AN: 37434

South Asian (SAS) AF: 0.000894 AC: 74 AN: 82762

European-Finnish (FIN) AF: 0.00271 AC: 104 AN: 38392

Middle Eastern (MID) AF: 0.000397 AC: 2 AN: 5038

European-Non Finnish (NFE) AF: 0.00194 AC: 2141 AN: 1103164

Other (OTH) AF: 0.00111 AC: 66 AN: 59330

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.00126 AC XY: 94 AN XY: 74480

African (AFR) AF: 0.000144 AC: 6 AN: 41586

American (AMR) AF: 0.000914 AC: 14 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00181 AC: 123 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.000835

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Benign	0.91
PhyloP100		0.38
PromoterAI		-0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
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: rs138862255; hg19: chr14-70346416;