rs4585442

Variant names:

• chr5-136172692-A-G
• rs4585442
• NM_005903.7:c.997+37A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005903.7. 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
	SMAD5	NM_005903.7	MANE Select	c.997+37A>G		intron	N/A	NP_005894.3
	SMAD5	NM_001001419.3		c.997+37A>G		intron	N/A	NP_001001419.1	Q99717
	SMAD5	NM_001001420.3		c.997+37A>G		intron	N/A	NP_001001420.1	Q99717

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD5	ENST00000545279.6	TSL:1 MANE Select	c.997+37A>G		intron	N/A	ENSP00000441954.2	Q99717
	SMAD5	ENST00000509297.6	TSL:1	c.997+37A>G		intron	N/A	ENSP00000426696.2	Q99717
	SMAD5	ENST00000507637.1	TSL:2	c.500A>G	p.Asn167Ser	missense	Exon 3 of 3	ENSP00000427474.1	H0YAK7

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

GnomAD2 exomes AF: 0.310 AC: 76384 AN: 246526 AF XY: 0.304

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 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

African (AFR) AF: 0.528 AC: 14951 AN: 28300

American (AMR) AF: 0.256 AC: 11332 AN: 44308

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 8524 AN: 24350

East Asian (EAS) AF: 0.366 AC: 14087 AN: 38512

South Asian (SAS) AF: 0.214 AC: 17253 AN: 80700

European-Finnish (FIN) AF: 0.310 AC: 16440 AN: 52966

Middle Eastern (MID) AF: 0.346 AC: 1829 AN: 5288

European-Non Finnish (NFE) AF: 0.307 AC: 270196 AN: 879942

Other (OTH) AF: 0.321 AC: 16734 AN: 52066

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

African (AFR) AF: 0.523 AC: 21701 AN: 41460

American (AMR) AF: 0.286 AC: 4373 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1195 AN: 3462

East Asian (EAS) AF: 0.377 AC: 1953 AN: 5184

South Asian (SAS) AF: 0.211 AC: 1020 AN: 4824

European-Finnish (FIN) AF: 0.305 AC: 3224 AN: 10568

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.299 AC: 20335 AN: 67962

Other (OTH) AF: 0.388 AC: 819 AN: 2110

Alfa AF: 0.384 Hom.: 4044

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.30
PhyloP100		-0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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