5-136160885-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_005903.7(SMAD5):c.433A>G(p.Asn145Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,632 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMAD5 NM_005903.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

SMAD5 (HGNC:6771): (SMAD family member 5) The protein encoded by this gene is involved in the transforming growth factor beta signaling pathway that results in an inhibition of the proliferation of hematopoietic progenitor cells. The encoded protein is activated by bone morphogenetic proteins type 1 receptor kinase, and may be involved in cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMAD5
• BP4: Computational evidence support a benign effect (MetaRNN=0.2705139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD5	NM_005903.7	c.433A>G	p.Asn145Asp	missense_variant	4/8	ENST00000545279.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD5	ENST00000545279.6	c.433A>G	p.Asn145Asp	missense_variant	4/8	1	NM_005903.7	P1
SMAD5	ENST00000509297.6	c.433A>G	p.Asn145Asp	missense_variant	4/8	1		P1
SMAD5	ENST00000545620.5	c.433A>G	p.Asn145Asp	missense_variant	3/7	5		P1
SMAD5	ENST00000514777.1	n.60-11549A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249180 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135188

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00000137 AC: 2 AN: 1461632 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2021

The c.433A>G (p.N145D) alteration is located in exon 5 (coding exon 2) of the SMAD5 gene. This alteration results from a A to G substitution at nucleotide position 433, causing the asparagine (N) at amino acid position 145 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.032
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Uncertain	-0.012	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	0.92	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.81	N;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.049	D;D;.
Sift4G	Benign	0.30	T;T;.
Vest4		0.19
MutPred		0.34		Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);Gain of relative solvent accessibility (P = 0.0249);
MVP		0.73
MPC		1.3
ClinPred		0.45	T
GERP RS		4.3
Varity_R		0.43
gMVP		0.15

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: rs1039692154; hg19: chr5-135496574;