rs6694035

Variant names:

• chr1-114716959-T-C
• rs6694035
• NM_001007553.3:c.*1210A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-114716959-T-C
• chr1-114716959-T-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001007553.3(CSDE1):​c.*1210A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0083 in 152,800 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: CSDE1 NM_001007553.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.29
• Publications: 4 publications found

Genes affected

CSDE1 (HGNC:29905): (cold shock domain containing E1) Enables RNA stem-loop binding activity. Involved in IRES-dependent viral translational initiation; nuclear-transcribed mRNA catabolic process, no-go decay; and stress granule assembly. Located in Golgi apparatus; cytosol; and plasma membrane. Part of CRD-mediated mRNA stability complex. [provided by Alliance of Genome Resources, Apr 2022]

NRAS (HGNC:7989): (NRAS proto-oncogene, GTPase) This is an N-ras oncogene encoding a membrane protein that shuttles between the Golgi apparatus and the plasma membrane. This shuttling is regulated through palmitoylation and depalmitoylation by the ZDHHC9-GOLGA7 complex. The encoded protein, which has intrinsic GTPase activity, is activated by a guanine nucleotide-exchange factor and inactivated by a GTPase activating protein. Mutations in this gene have been associated with somatic rectal cancer, follicular thyroid cancer, autoimmune lymphoproliferative syndrome, Noonan syndrome, and juvenile myelomonocytic leukemia. [provided by RefSeq, Jun 2011]

NRAS Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 6

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

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: ClinGen, Genomics England PanelApp
• Costello syndrome

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

  Inheritance: AD Classification: LIMITED 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-114716959-T-C is Benign according to our data. Variant chr1-114716959-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1202429.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00832 (1268/152370) while in subpopulation NFE AF = 0.0143 (972/68042). AF 95% confidence interval is 0.0135. There are 7 homozygotes in GnomAd4. There are 561 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1268 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007553.3. 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
	CSDE1	NM_001007553.3	MANE Select	c.*1210A>G		3_prime_UTR	Exon 20 of 20	NP_001007554.1	O75534-1
	CSDE1	NM_001242891.2		c.*1210A>G		3_prime_UTR	Exon 21 of 21	NP_001229820.1	O75534-4
	CSDE1	NM_001130523.3		c.*1210A>G		3_prime_UTR	Exon 20 of 20	NP_001123995.1	O75534-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSDE1	ENST00000358528.9	TSL:1 MANE Select	c.*1210A>G		3_prime_UTR	Exon 20 of 20	ENSP00000351329.4	O75534-1
	CSDE1	ENST00000438362.7	TSL:1	c.*1210A>G		3_prime_UTR	Exon 21 of 21	ENSP00000407724.3	O75534-1
	CSDE1	ENST00000339438.10	TSL:1	c.*1210A>G		3_prime_UTR	Exon 19 of 19	ENSP00000342408.6	O75534-2

Frequencies

GnomAD3 genomes AF: 0.00833 AC: 1268 AN: 152252 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00562

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.00863

GnomAD4 exome AF: 0.00233 AC: 1 AN: 430 Hom.: 0 Cov.: 0 AF XY: 0.00388 AC XY: 1 AN XY: 258

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00244 AC: 1 AN: 410

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.00832 AC: 1268 AN: 152370 Hom.: 7 Cov.: 33 AF XY: 0.00753 AC XY: 561 AN XY: 74516

African (AFR) AF: 0.00257 AC: 107 AN: 41582

American (AMR) AF: 0.00562 AC: 86 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00518 AC: 55 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0143 AC: 972 AN: 68042

Other (OTH) AF: 0.00854 AC: 18 AN: 2108

Alfa AF: 0.00497 Hom.: 0

Bravo AF: 0.00791

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Benign	0.85
PhyloP100		3.3
PromoterAI		0.073	Neutral
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: rs6694035; hg19: chr1-115259580;