rs1555405092

Variant names:

• chr15-67066155-A-C
• rs1555405092
• NM_005902.4:c.1A>C

Your query was ambiguous. Multiple possible variants found:

• chr15-67066155-A-C
• chr15-67066155-A-G
• chr15-67066155-A-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_005902.4(SMAD3):​c.1A>C​(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.00000208 in 1,439,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SMAD3 NM_005902.4 initiator_codon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.97
• Publications: 0 publications found

Genes affected

SMAD3 (HGNC:6769): (SMAD family member 3) The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3. [provided by RefSeq, May 2022]

SMAD3 Gene-Disease associations (from GenCC):

• aneurysm-osteoarthritis syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 45 pathogenic variants. Next in-frame start position is after 106 codons. Genomic position: 67165004. Lost 0.247 part of the original CDS.
• PS1: Another start lost variant in NM_005902.4 (SMAD3) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-67066155-A-C is Pathogenic according to our data. Variant chr15-67066155-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 520186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005902.4. 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
	SMAD3	NM_005902.4	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	NP_001393940.1	H3BQ00
	SMAD3	NM_001407012.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 8	NP_001393941.1	A0AAQ5BHI7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000560424.2	TSL:3	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	ENSP00000455540.2	H3BQ00
	SMAD3	ENST00000714110.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000519402.1	A0AAQ5BHK2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1439970 Hom.: 0 Cov.: 33 AF XY: 0.00000280 AC XY: 2 AN XY: 714348

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000303 AC: 1 AN: 32978

American (AMR) AF: 0.00 AC: 0 AN: 42042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25728

East Asian (EAS) AF: 0.00 AC: 0 AN: 38716

South Asian (SAS) AF: 0.00 AC: 0 AN: 83258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4392

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102300

Other (OTH) AF: 0.00 AC: 0 AN: 59438

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00462622), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Familial thoracic aortic aneurysm and aortic dissection (2)
1	-	-	Aneurysm-osteoarthritis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.18	D
PhyloP100		5.0
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.54
Sift	Benign	0.35	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.82
MutPred		0.99		Loss of sheet (P = 0.1907)
MVP		0.98
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.19
gMVP		0.32
Mutation Taster		=8/192	disease causing (ClinVar)

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: rs1555405092; hg19: chr15-67358493;