NM_019108.4:c.1290G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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]

SMG9 Gene-Disease associations (from GenCC):

• heart and brain malformation syndrome

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 28 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019108.4. 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
	SMG9	NM_019108.4	MANE Select	c.1290G>A	p.Leu430Leu	synonymous	Exon 12 of 14	NP_061981.2	Q9H0W8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMG9	ENST00000270066.11	TSL:1 MANE Select	c.1290G>A	p.Leu430Leu	synonymous	Exon 12 of 14	ENSP00000270066.6	Q9H0W8-1
	SMG9	ENST00000892518.1		c.1383G>A	p.Leu461Leu	synonymous	Exon 12 of 14	ENSP00000562577.1
	SMG9	ENST00000892519.1		c.1356G>A	p.Leu452Leu	synonymous	Exon 12 of 14	ENSP00000562578.1

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

GnomAD2 exomes AF: 0.00451 AC: 1135 AN: 251480 AF XY: 0.00478

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 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

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00454 AC: 203 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 331 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00893 AC: 770 AN: 86254

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53410

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.00505 AC: 5615 AN: 1112002

Other (OTH) AF: 0.00584 AC: 353 AN: 60396

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

African (AFR) AF: 0.00128 AC: 53 AN: 41510

American (AMR) AF: 0.00844 AC: 129 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4810

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10600

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00440 AC: 299 AN: 68026

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00455 Hom.: 1

Bravo AF: 0.00421

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00575

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.2
DANN	Benign	0.65
PhyloP100		-0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs144177272; hg19: chr19-44237525;