rs4585442

Positions:

• chr5-136172692-A-G

Variant summary

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

The NM_005903.7(SMAD5):​c.997+37A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 1,358,494 control chromosomes in the GnomAD database, including 70,292 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 (10714 hom., cov: 33)
  • Exomes 𝑓: 0.31 (59578 hom.)
• Consequence: SMAD5 NM_005903.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.114

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 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 = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD5	NM_005903.7	c.997+37A>G		intron_variant		ENST00000545279.6	NP_005894.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD5	ENST00000545279.6	c.997+37A>G		intron_variant		1	NM_005903.7	ENSP00000441954	P1

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54834 AN: 151942 Hom.: 10690 Cov.: 33

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.386

GnomAD3 exomes AF: 0.310 AC: 76384 AN: 246526 Hom.: 12656 AF XY: 0.304 AC XY: 40713 AN XY: 133744

Gnomad AFR exome AF: 0.528

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.353

Gnomad EAS exome AF: 0.392

Gnomad SAS exome AF: 0.214

Gnomad FIN exome AF: 0.314

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.309

GnomAD4 exome AF: 0.308 AC: 371346 AN: 1206432 Hom.: 59578 Cov.: 16 AF XY: 0.305 AC XY: 186770 AN XY: 613302

Gnomad4 AFR exome AF: 0.528

Gnomad4 AMR exome AF: 0.256

Gnomad4 ASJ exome AF: 0.350

Gnomad4 EAS exome AF: 0.366

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.310

Gnomad4 NFE exome AF: 0.307

Gnomad4 OTH exome AF: 0.321

GnomAD4 genome AF: 0.361 AC: 54902 AN: 152062 Hom.: 10714 Cov.: 33 AF XY: 0.357 AC XY: 26528 AN XY: 74360

Gnomad4 AFR AF: 0.523

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.345

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.305

Gnomad4 NFE AF: 0.299

Gnomad4 OTH AF: 0.388

Alfa AF: 0.331 Hom.: 2025

Bravo AF: 0.373

Asia WGS AF: 0.352 AC: 1226 AN: 3478

EpiCase AF: 0.312

EpiControl AF: 0.326

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs4585442; hg19: chr5-135508381; COSMIC: COSV72596973; COSMIC: COSV72596973;