Genetic Variant KRAS:c.*4187delA (chr12-25205728-CT-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_004985.5(KRAS):c.*4066delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0042 ( 9 hom., cov: 0)

Exomes 𝑓: 0.00087 ( 0 hom. )

Consequence

KRAS
NM_004985.5 3_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.12

Publications

1 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 -9 ACMG points.

BP6

Variant 12-25205728-CT-C is Benign according to our data. Variant chr12-25205728-CT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 308061.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00424 (644/151750) while in subpopulation AFR AF = 0.0149 (616/41410). AF 95% confidence interval is 0.0139. There are 9 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 644 AD gene.

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.*4187delA	3_prime_UTR	Exon 6 of 6	NP_203524.1	P01116-1
KRAS	NM_004985.5	MANE Select	c.*4066delA	3_prime_UTR	Exon 5 of 5	NP_004976.2
KRAS	NM_001369786.1		c.*4187delA	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.*4187delA	3_prime_UTR	Exon 6 of 6	ENSP00000256078.5	P01116-1
KRAS	ENST00000311936.8	TSL:1 MANE Select	c.*4066delA	3_prime_UTR	Exon 5 of 5	ENSP00000308495.3	P01116-2
KRAS	ENST00000685328.1		c.*4066delA	3_prime_UTR	Exon 5 of 5	ENSP00000508921.1	P01116-2

Frequencies

GnomAD3 genomes

AF:

0.00423

AC:

641

AN:

151632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0148

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00192

GnomAD4 exome

AF:

0.000871

AC:

AN:

68906

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

31890

show subpopulations

African (AFR)

AF:

0.0130

AC:

AN:

3372

American (AMR)

AF:

0.00145

AC:

AN:

2076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4334

East Asian (EAS)

AF:

0.00

AC:

AN:

9748

South Asian (SAS)

AF:

0.00

AC:

AN:

596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

432

European-Non Finnish (NFE)

AF:

0.0000470

AC:

AN:

42526

Other (OTH)

AF:

0.00191

AC:

AN:

5762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00424

AC:

644

AN:

151750

Hom.:

Cov.:

AF XY:

0.00433

AC XY:

321

AN XY:

74142

show subpopulations

African (AFR)

AF:

0.0149

AC:

616

AN:

41410

American (AMR)

AF:

0.00151

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67844

Other (OTH)

AF:

0.00190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00

Hom.:

1051

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardio-facio-cutaneous syndrome (1)

Noonan syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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12-25205728-CTTTT-CTTT

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