Genetic Variant NM_001136023.3:c.115-67T>G (chr12-54293448-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001136023.3(NFE2):c.115-67T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 1,383,724 control chromosomes in the GnomAD database, including 329,763 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.76 ( 45023 hom., cov: 32)

Exomes 𝑓: 0.67 ( 284740 hom. )

Consequence

NFE2
NM_001136023.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.302

Publications

48 publications found

Variant links:

Genes affected

NFE2 (HGNC:7780): (nuclear factor, erythroid 2) Enables several functions, including WW domain binding activity; identical protein binding activity; and protein N-terminus binding activity. Contributes to cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including labyrinthine layer blood vessel development; negative regulation of bone mineralization; and negative regulation of syncytium formation by plasma membrane fusion. Part of protein-DNA complex. [provided by Alliance of Genome Resources, Apr 2022]

NFE2 links:

ENSG00000258344 (HGNC:):

ENSG00000258344 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFE2	NM_001136023.3 link	c.115-67T>G		intron_variant	Intron 2 of 2	ENST00000435572.7	NP_001129495.1	Q16621A8K3E0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFE2	ENST00000435572.7 link	c.115-67T>G		intron_variant	Intron 2 of 2	1	NM_001136023.3	ENSP00000397185.2		Q16621

Frequencies

GnomAD3 genomes

AF:

0.756

AC:

114899

AN:

152048

Hom.:

44953

Cov.:

show subpopulations

Gnomad AFR

AF:

0.937

Gnomad AMI

AF:

0.493

Gnomad AMR

AF:

0.754

Gnomad ASJ

AF:

0.593

Gnomad EAS

AF:

0.997

Gnomad SAS

AF:

0.883

Gnomad FIN

AF:

0.746

Gnomad MID

AF:

0.604

Gnomad NFE

AF:

0.633

Gnomad OTH

AF:

0.718

GnomAD4 exome

AF:

0.673

AC:

829408

AN:

1231558

Hom.:

284740

AF XY:

0.674

AC XY:

400965

AN XY:

595258

show subpopulations

African (AFR)

AF:

0.950

AC:

26481

AN:

27866

American (AMR)

AF:

0.818

AC:

19114

AN:

23372

Ashkenazi Jewish (ASJ)

AF:

0.589

AC:

9963

AN:

16916

East Asian (EAS)

AF:

0.999

AC:

34624

AN:

34646

South Asian (SAS)

AF:

0.877

AC:

37746

AN:

43020

European-Finnish (FIN)

AF:

0.745

AC:

32734

AN:

43942

Middle Eastern (MID)

AF:

0.672

AC:

3243

AN:

4828

European-Non Finnish (NFE)

AF:

0.639

AC:

630472

AN:

987164

Other (OTH)

AF:

0.703

AC:

35031

AN:

49804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

13401

26802

40203

53604

67005

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18654

37308

55962

74616

93270

<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:

0.756

AC:

115030

AN:

152166

Hom.:

45023

Cov.:

AF XY:

0.764

AC XY:

56859

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.938

AC:

38941

AN:

41532

American (AMR)

AF:

0.755

AC:

11522

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.593

AC:

2057

AN:

3470

East Asian (EAS)

AF:

0.997

AC:

5168

AN:

5182

South Asian (SAS)

AF:

0.882

AC:

4263

AN:

4832

European-Finnish (FIN)

AF:

0.746

AC:

7901

AN:

10586

Middle Eastern (MID)

AF:

0.612

AC:

180

AN:

294

European-Non Finnish (NFE)

AF:

0.633

AC:

43032

AN:

67990

Other (OTH)

AF:

0.721

AC:

1519

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1306

2613

3919

5226

6532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

848

1696

2544

3392

4240

<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:

0.674

Hom.:

149622

Bravo

AF:

0.764

Asia WGS

AF:

0.942

AC:

3274

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

9.3

(source)

DANN

Benign

0.71

PhyloP100

-0.30

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over