chr15-66703378-C-T

Position:

• chr15-66703378-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005585.5(SMAD6):​c.120C>T​(p.Gly40Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 1,454,994 control chromosomes in the GnomAD database, including 1,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (91 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1063 hom.)
• Consequence: SMAD6 NM_005585.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.77

Genes affected

SMAD6 (HGNC:6772): (SMAD family member 6) The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila 'mothers against decapentaplegic' (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.[provided by RefSeq, Sep 2014]

SMAD6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 15-66703378-C-T is Benign according to our data. Variant chr15-66703378-C-T is described in ClinVar as [Benign]. Clinvar id is 240176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-66703378-C-T is described in Lovd as [Benign]. Variant chr15-66703378-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0295 (4479/151964) while in subpopulation NFE AF= 0.0436 (2961/67898). AF 95% confidence interval is 0.0423. There are 91 homozygotes in gnomad4. There are 2189 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4479 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.120C>T	p.Gly40Gly	synonymous_variant	1/4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.1143C>T		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.1143C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.120C>T	p.Gly40Gly	synonymous_variant	1/4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.120C>T		non_coding_transcript_exon_variant	1/5	1		ENSP00000452955.1
SMAD6	ENST00000612349.1	n.302C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4482 AN: 151856 Hom.: 91 Cov.: 32

Gnomad AFR AF: 0.00718

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.000583

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0436

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0364 AC: 2487 AN: 68238 Hom.: 52 AF XY: 0.0353 AC XY: 1332 AN XY: 37758

Gnomad AFR exome AF: 0.00627

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.0734

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00770

Gnomad FIN exome AF: 0.0505

Gnomad NFE exome AF: 0.0462

Gnomad OTH exome AF: 0.0377

GnomAD4 exome AF: 0.0371 AC: 48392 AN: 1303030 Hom.: 1063 Cov.: 32 AF XY: 0.0369 AC XY: 23639 AN XY: 640752

Gnomad4 AFR exome AF: 0.00445

Gnomad4 AMR exome AF: 0.0237

Gnomad4 ASJ exome AF: 0.0670

Gnomad4 EAS exome AF: 0.0000712

Gnomad4 SAS exome AF: 0.00735

Gnomad4 FIN exome AF: 0.0488

Gnomad4 NFE exome AF: 0.0403

Gnomad4 OTH exome AF: 0.0323

GnomAD4 genome AF: 0.0295 AC: 4479 AN: 151964 Hom.: 91 Cov.: 32 AF XY: 0.0295 AC XY: 2189 AN XY: 74290

Gnomad4 AFR AF: 0.00716

Gnomad4 AMR AF: 0.0223

Gnomad4 ASJ AF: 0.0588

Gnomad4 EAS AF: 0.000585

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.0535

Gnomad4 NFE AF: 0.0436

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0203 Hom.: 20

Bravo AF: 0.0271

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -

Aortic valve disease 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149612008; hg19: chr15-66995716;