chr14-50118294-A-T

Variant names:

• chr14-50118294-A-T
• rs74714090
• NM_006939.4:c.*50T>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_006939.4(SOS2):​c.*50T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00418 in 1,469,722 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (35 hom.)
• Consequence: SOS2 NM_006939.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.63
• Publications: 3 publications found

Genes affected

SOS2 (HGNC:11188): (SOS Ras/Rho guanine nucleotide exchange factor 2) This gene encodes a regulatory protein that is involved in the positive regulation of ras proteins. Mutations in this gene are associated with Noonan Syndrome-9. [provided by RefSeq, Jul 2016]

SOS2 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 14-50118294-A-T is Benign according to our data. Variant chr14-50118294-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1202548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00428 (5636/1317370) while in subpopulation SAS AF = 0.0169 (1159/68692). AF 95% confidence interval is 0.0161. There are 35 homozygotes in GnomAdExome4. There are 3027 alleles in the male GnomAdExome4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High AC in GnomAd4 at 502 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006939.4. 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
	SOS2	NM_006939.4	MANE Select	c.*50T>A		3_prime_UTR	Exon 23 of 23	NP_008870.2	Q07890-1
	SOS2	NM_001411020.1		c.*50T>A		3_prime_UTR	Exon 22 of 22	NP_001397949.1	Q07890-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	ENST00000216373.10	TSL:1 MANE Select	c.*50T>A		3_prime_UTR	Exon 23 of 23	ENSP00000216373.5	Q07890-1
	SOS2	ENST00000934708.1		c.*50T>A		3_prime_UTR	Exon 24 of 24	ENSP00000604767.1
	SOS2	ENST00000953731.1		c.*50T>A		3_prime_UTR	Exon 24 of 24	ENSP00000623790.1

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 503 AN: 152234 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00404 AC: 745 AN: 184588 AF XY: 0.00453

Gnomad AFR exome AF: 0.000553

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00993

Gnomad EAS exome AF: 0.000128

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00428 AC: 5636 AN: 1317370 Hom.: 35 Cov.: 19 AF XY: 0.00466 AC XY: 3027 AN XY: 649098

African (AFR) AF: 0.000482 AC: 14 AN: 29066

American (AMR) AF: 0.00156 AC: 45 AN: 28810

Ashkenazi Jewish (ASJ) AF: 0.00791 AC: 160 AN: 20228

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38470

South Asian (SAS) AF: 0.0169 AC: 1159 AN: 68692

European-Finnish (FIN) AF: 0.00284 AC: 142 AN: 50026

Middle Eastern (MID) AF: 0.00977 AC: 51 AN: 5220

European-Non Finnish (NFE) AF: 0.00372 AC: 3805 AN: 1022384

Other (OTH) AF: 0.00475 AC: 259 AN: 54474

GnomAD4 genome AF: 0.00330 AC: 502 AN: 152352 Hom.: 3 Cov.: 32 AF XY: 0.00346 AC XY: 258 AN XY: 74498

African (AFR) AF: 0.000673 AC: 28 AN: 41576

American (AMR) AF: 0.00150 AC: 23 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4820

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00435 AC: 296 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00414 Hom.: 1

Bravo AF: 0.00258

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.0
DANN	Benign	0.79
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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: rs74714090; hg19: chr14-50585012; COSMIC: COSV107242211; COSMIC: COSV107242211;