NM_006939.4:c.1071A>T

Variant names:

• chr14-50161607-T-A
• NM_006939.4:c.1071A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_006939.4(SOS2):​c.1071A>T​(p.Gln357His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,442 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SOS2 NM_006939.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain DH (size 190) in uniprot entity SOS2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006939.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4	c.1071A>T	p.Gln357His	missense_variant, splice_region_variant	Exon 9 of 23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.1071A>T	p.Gln357His	missense_variant, splice_region_variant	Exon 9 of 23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.972A>T	p.Gln324His	missense_variant, splice_region_variant	Exon 8 of 22	1		ENSP00000445328.1
SOS2	ENST00000555794.2	c.183A>T	p.Gln61His	missense_variant, splice_region_variant	Exon 3 of 6	1		ENSP00000484766.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457442 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724828

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;T
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.46	T;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.68	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.68	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0060	B;.
Vest4		0.67
MutPred		0.57		Gain of ubiquitination at K356 (P = 0.102);.;
MVP		0.94
MPC		1.0
ClinPred		0.87	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.56

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-50628325;