rs6596284

Positions:

• chr5-136134855-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005903.7(SMAD5):​c.-245+1893T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 152,042 control chromosomes in the GnomAD database, including 10,819 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (10819 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: SMAD5 NM_005903.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.651

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]

SMAD5-AS1 (HGNC:30586): (SMAD5 antisense RNA 1) Predicted to be involved in signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD5	NM_005903.7	c.-245+1893T>C		intron_variant		ENST00000545279.6	NP_005894.3
SMAD5-AS1	NR_026763.1	n.36A>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD5	ENST00000545279.6	c.-245+1893T>C		intron_variant		1	NM_005903.7	ENSP00000441954	P1
SMAD5-AS1	ENST00000297163.3	n.36A>G		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54654 AN: 151918 Hom.: 10789 Cov.: 32

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.383

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 2 AN XY: 4

Gnomad4 FIN exome AF: 0.500

GnomAD4 genome AF: 0.360 AC: 54731 AN: 152038 Hom.: 10819 Cov.: 32 AF XY: 0.356 AC XY: 26420 AN XY: 74310

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.343

Gnomad4 EAS AF: 0.376

Gnomad4 SAS AF: 0.187

Gnomad4 FIN AF: 0.301

Gnomad4 NFE AF: 0.291

Gnomad4 OTH AF: 0.384

Alfa AF: 0.327 Hom.: 1439

Bravo AF: 0.374

Asia WGS AF: 0.344 AC: 1198 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.45

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: rs6596284; hg19: chr5-135470544;