rs368960350

chr15-66703397-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005585.5(SMAD6):c.139C>T(p.Pro47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000913 in 1,404,954 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P47L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.55

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005159676).
• BP6: Variant 15-66703397-C-T is Benign according to our data. Variant chr15-66703397-C-T is described in ClinVar as [Benign]. Clinvar id is 471749.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-66703397-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00501 (762/151958) while in subpopulation AFR AF= 0.0176 (729/41478). AF 95% confidence interval is 0.0165. There are 6 homozygotes in gnomad4. There are 342 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 759 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.139C>T	p.Pro47Ser	missense_variant	1/4	ENST00000288840.10
SMAD6	NR_027654.2	n.1162C>T		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.1162C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.139C>T	p.Pro47Ser	missense_variant	1/4	1	NM_005585.5	P1
SMAD6	ENST00000557916.5	c.139C>T	p.Pro47Ser	missense_variant, NMD_transcript_variant	1/5	1
SMAD6	ENST00000612349.1	n.321C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 759 AN: 151850 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000812 AC: 27 AN: 33256 Hom.: 0 AF XY: 0.000441 AC XY: 8 AN XY: 18142

Gnomad AFR exome AF: 0.0361

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000416 AC: 521 AN: 1252996 Hom.: 3 Cov.: 32 AF XY: 0.000375 AC XY: 230 AN XY: 613124

Gnomad4 AFR exome AF: 0.0176

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000692

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000693

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00501 AC: 762 AN: 151958 Hom.: 6 Cov.: 32 AF XY: 0.00460 AC XY: 342 AN XY: 74284

Gnomad4 AFR AF: 0.0176

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00354 Hom.: 1

Bravo AF: 0.00581

ESP6500AA AF: 0.00823 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000559 AC: 40

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic valve disease 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.88	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.12
Sift	Uncertain	0.012	D
Sift4G	Benign	0.39	T
Polyphen		0.0030	B
Vest4		0.17
MVP		0.59
MPC		1.1
ClinPred		0.021	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.077
gMVP		0.42

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: rs368960350; hg19: chr15-66995735;