Genetic Variant KRAS:c.*3623T>A (chr12-25206293-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004985.5(KRAS):c.*3502T>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 0.0216 in 208,276 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 88 hom., cov: 32)

Exomes 𝑓: 0.017 ( 13 hom. )

Consequence

KRAS
NM_004985.5 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.18

Publications

6 publications found

Variant links:

Genes affected

KRAS (HGNC:6407): (KRAS proto-oncogene, GTPase) This gene, a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. Alternative splicing leads to variants encoding two isoforms that differ in the C-terminal region. [provided by RefSeq, Jul 2008]

KRAS links:

ETFRF1 (HGNC:27052): (electron transfer flavoprotein regulatory factor 1) Involved in respiratory electron transport chain. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ETFRF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 12-25206293-A-T is Benign according to our data. Variant chr12-25206293-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 308072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004985.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KRAS	NM_033360.4	MANE Plus Clinical	c.*3623T>A	3_prime_UTR	Exon 6 of 6	NP_203524.1	P01116-1
KRAS	NM_004985.5	MANE Select	c.*3502T>A	3_prime_UTR	Exon 5 of 5	NP_004976.2
KRAS	NM_001369786.1		c.*3623T>A	3_prime_UTR	Exon 6 of 6	NP_001356715.1	P01116-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.*3623T>A	3_prime_UTR	Exon 6 of 6	ENSP00000256078.5	P01116-1
KRAS	ENST00000311936.8	TSL:1 MANE Select	c.*3502T>A	3_prime_UTR	Exon 5 of 5	ENSP00000308495.3	P01116-2
KRAS	ENST00000685328.1		c.*3502T>A	3_prime_UTR	Exon 5 of 5	ENSP00000508921.1	P01116-2

Frequencies

GnomAD3 genomes

AF:

0.0233

AC:

3547

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0418

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.0600

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0922

Gnomad FIN

AF:

0.00414

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0130

Gnomad OTH

AF:

0.0239

GnomAD4 exome

AF:

0.0169

AC:

946

AN:

56026

Hom.:

Cov.:

AF XY:

0.0169

AC XY:

438

AN XY:

25952

show subpopulations

African (AFR)

AF:

0.0389

AC:

100

AN:

2574

American (AMR)

AF:

0.0113

AC:

AN:

1678

Ashkenazi Jewish (ASJ)

AF:

0.0647

AC:

220

AN:

3398

East Asian (EAS)

AF:

0.00

AC:

AN:

8226

South Asian (SAS)

AF:

0.0721

AC:

AN:

458

European-Finnish (FIN)

AF:

0.00429

AC:

AN:

466

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

348

European-Non Finnish (NFE)

AF:

0.0139

AC:

477

AN:

34248

Other (OTH)

AF:

0.0192

AC:

AN:

4630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0234

AC:

3556

AN:

152250

Hom.:

Cov.:

AF XY:

0.0248

AC XY:

1846

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0419

AC:

1740

AN:

41532

American (AMR)

AF:

0.0116

AC:

178

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0600

AC:

208

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0925

AC:

446

AN:

4824

European-Finnish (FIN)

AF:

0.00414

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0130

AC:

882

AN:

68010

Other (OTH)

AF:

0.0237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

169

338

506

675

844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0181

Hom.:

Bravo

AF:

0.0237

Asia WGS

AF:

0.0350

AC:

121

AN:

3470

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Noonan syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over