rs144177272

Variant names:

• chr19-43733373-C-T
• rs144177272
• NM_019108.4:c.1290G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_019108.4(SMG9):​c.1290G>A​(p.Leu430Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00494 in 1,614,076 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (28 hom.)
• Consequence: SMG9 NM_019108.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.278

Genes affected

SMG9 (HGNC:25763): (SMG9 nonsense mediated mRNA decay factor) This gene encodes a regulatory subunit of the SMG1 complex, which plays a critical role in nonsense-mediated mRNA decay (NMD). Binding of the encoded protein to the SMG1 complex kinase scaffold protein results in the inhibition of its kinase activity. Mutations in this gene cause a multiple congenital anomaly syndrome in human patients, characterized by brain malformation, congenital heart disease and other features. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 19-43733373-C-T is Benign according to our data. Variant chr19-43733373-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 713846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.278 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.004 (609/152206) while in subpopulation SAS AF= 0.0106 (51/4810). AF 95% confidence interval is 0.00828. There are 1 homozygotes in gnomad4. There are 294 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMG9	NM_019108.4	c.1290G>A	p.Leu430Leu	synonymous_variant	Exon 12 of 14	ENST00000270066.11	NP_061981.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMG9	ENST00000270066.11	c.1290G>A	p.Leu430Leu	synonymous_variant	Exon 12 of 14	1	NM_019108.4	ENSP00000270066.6
SMG9	ENST00000601170.5	c.1290G>A	p.Leu430Leu	synonymous_variant	Exon 12 of 13	2		ENSP00000471398.1
SMG9	ENST00000594081.1	n.534G>A		non_coding_transcript_exon_variant	Exon 2 of 2	4
SMG9	ENST00000598860.1	n.*51G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 611 AN: 152088 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00845

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00439

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00451 AC: 1135 AN: 251480 Hom.: 6 AF XY: 0.00478 AC XY: 650 AN XY: 135914

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00934

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00446

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00504 AC: 7366 AN: 1461870 Hom.: 28 Cov.: 31 AF XY: 0.00525 AC XY: 3817 AN XY: 727244

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00454

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00893

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.00505

Gnomad4 OTH exome AF: 0.00584

GnomAD4 genome AF: 0.00400 AC: 609 AN: 152206 Hom.: 1 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74406

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00844

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00440

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00473 Hom.: 1

Bravo AF: 0.00421

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00575

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMG9: BP4, BP7, BS2 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.2
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs144177272; hg19: chr19-44237525;