rs1203972910

Variant names:

• chr18-51065404-T-C
• rs1203972910
• NM_005359.6:c.956-19T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_005359.6(SMAD4):​c.956-19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,601,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0810
• Publications: 0 publications found

Genes affected

SMAD4 (HGNC:6770): (SMAD family member 4) This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasing blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome. [provided by RefSeq, May 2022]

SMAD4 Gene-Disease associations (from GenCC):

• juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
• Myhre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• generalized juvenile polyposis/juvenile polyposis coli

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• juvenile polyposis syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 18-51065404-T-C is Benign according to our data. Variant chr18-51065404-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 492504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005359.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	NM_005359.6	MANE Select	c.956-19T>C		intron	N/A	NP_005350.1
	SMAD4	NM_001407041.1		c.956-19T>C		intron	N/A	NP_001393970.1
	SMAD4	NM_001407042.1		c.956-19T>C		intron	N/A	NP_001393971.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	ENST00000342988.8	TSL:5 MANE Select	c.956-19T>C		intron	N/A	ENSP00000341551.3
	SMAD4	ENST00000591126.5	TSL:1	n.2957-19T>C		intron	N/A
	SMAD4	ENST00000714264.1		c.1018T>C	p.Ser340Pro	missense	Exon 9 of 12	ENSP00000519545.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151840 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449986 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 722046

African (AFR) AF: 0.00 AC: 0 AN: 33286

American (AMR) AF: 0.00 AC: 0 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1101934

Other (OTH) AF: 0.00 AC: 0 AN: 59934

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151840 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74182

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67888

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Juvenile polyposis syndrome (1)
-	-	1	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		0.081
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1203972910; hg19: chr18-48591774;