chr5-136163522-T-C

Variant names:

• chr5-136163522-T-C
• rs1109158
• NM_005903.7:c.775+131T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005903.7(SMAD5):​c.775+131T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 460,566 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SMAD5 NM_005903.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.103
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

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.775+131T>C		intron	N/A	NP_005894.3
	SMAD5	NM_001001419.3		c.775+131T>C		intron	N/A	NP_001001419.1
	SMAD5	NM_001001420.3		c.775+131T>C		intron	N/A	NP_001001420.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD5	ENST00000545279.6	TSL:1 MANE Select	c.775+131T>C		intron	N/A	ENSP00000441954.2
	SMAD5	ENST00000509297.6	TSL:1	c.775+131T>C		intron	N/A	ENSP00000426696.2
	SMAD5	ENST00000545620.5	TSL:5	c.775+131T>C		intron	N/A	ENSP00000446474.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000217 AC: 1 AN: 460566 Hom.: 0 AF XY: 0.00000424 AC XY: 1 AN XY: 235684

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 10176

American (AMR) AF: 0.00 AC: 0 AN: 10666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11826

East Asian (EAS) AF: 0.00 AC: 0 AN: 25464

South Asian (SAS) AF: 0.00 AC: 0 AN: 25246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1884

European-Non Finnish (NFE) AF: 0.00000318 AC: 1 AN: 314422

Other (OTH) AF: 0.00 AC: 0 AN: 24414

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.7
DANN	Benign	0.54
PhyloP100		0.10

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: rs1109158; hg19: chr5-135499211;