rs373376338

chr15-66703482-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005585.5(SMAD6):c.224G>A(p.Arg75Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,237,406 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.09

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06083551).
• BP6: Variant 15-66703482-G-A is Benign according to our data. Variant chr15-66703482-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 471752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000324 (49/151410) while in subpopulation EAS AF= 0.00783 (40/5108). AF 95% confidence interval is 0.00591. There are 1 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.224G>A	p.Arg75Gln	missense_variant	1/4	ENST00000288840.10
SMAD6	NR_027654.2	n.1247G>A		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.1247G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.224G>A	p.Arg75Gln	missense_variant	1/4	1	NM_005585.5	P1
SMAD6	ENST00000557916.5	c.224G>A	p.Arg75Gln	missense_variant, NMD_transcript_variant	1/5	1
SMAD6	ENST00000612349.1	n.406G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000330 AC: 50 AN: 151304 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00800

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000738

Gnomad OTH AF: 0.000481

GnomAD4 exome AF: 0.000168 AC: 182 AN: 1085996 Hom.: 2 Cov.: 31 AF XY: 0.000134 AC XY: 69 AN XY: 514186

Gnomad4 AFR exome AF: 0.0000445

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00418

Gnomad4 SAS exome AF: 0.000101

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000653

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.000324 AC: 49 AN: 151410 Hom.: 1 Cov.: 32 AF XY: 0.000297 AC XY: 22 AN XY: 74014

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00783

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000738

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000366

ExAC AF: 0.000127 AC: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SMAD6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Aortic valve disease 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.94	D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.19
Sift	Benign	0.10	T
Sift4G	Benign	0.12	T
Polyphen		0.96	D
Vest4		0.15
MutPred		0.41		Loss of methylation at R75 (P = 0.0231);
MVP		0.82
MPC		1.5
ClinPred		0.77	D
GERP RS		3.5
Varity_R		0.16
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs373376338; hg19: chr15-66995820;