Genetic Variant RET:p.Ala45Ala (chr10-43100520-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020975.6(RET):c.135A>G(p.Ala45Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 1,613,574 control chromosomes in the GnomAD database, including 451,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A45A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.79 ( 47935 hom., cov: 32)

Exomes 𝑓: 0.74 ( 403068 hom. )

Consequence

RET
NM_020975.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -2.19

Publications

96 publications found

Variant links:

Genes affected

RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

RET Gene-Disease associations (from GenCC):

familial medullary thyroid carcinoma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
multiple endocrine neoplasia type 2A
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
multiple endocrine neoplasia type 2B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
pheochromocytoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Hirschsprung disease, susceptibility to, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Haddad syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hirschsprung disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
bilateral renal agenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
renal agenesis
Inheritance: AR Classification: LIMITED Submitted by: G2P

RET links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 10-43100520-A-G is Benign according to our data. Variant chr10-43100520-A-G is described in ClinVar as Benign. ClinVar VariationId is 167589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.19 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.941 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020975.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RET	NM_020975.6	MANE Select	c.135A>G	p.Ala45Ala	synonymous	Exon 2 of 20	NP_066124.1	P07949-1
RET	NM_001406743.1		c.135A>G	p.Ala45Ala	synonymous	Exon 2 of 21	NP_001393672.1	P07949-1
RET	NM_001406744.1		c.135A>G	p.Ala45Ala	synonymous	Exon 2 of 20	NP_001393673.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RET	ENST00000355710.8	TSL:5 MANE Select	c.135A>G	p.Ala45Ala	synonymous	Exon 2 of 20	ENSP00000347942.3	P07949-1
RET	ENST00000340058.6	TSL:1	c.135A>G	p.Ala45Ala	synonymous	Exon 2 of 19	ENSP00000344798.4	P07949-2
RET	ENST00000713926.1		c.135A>G	p.Ala45Ala	synonymous	Exon 2 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes

AF:

0.785

AC:

119303

AN:

151974

Hom.:

47871

Cov.:

show subpopulations

Gnomad AFR

AF:

0.949

Gnomad AMI

AF:

0.834

Gnomad AMR

AF:

0.756

Gnomad ASJ

AF:

0.701

Gnomad EAS

AF:

0.548

Gnomad SAS

AF:

0.707

Gnomad FIN

AF:

0.638

Gnomad MID

AF:

0.715

Gnomad NFE

AF:

0.742

Gnomad OTH

AF:

0.773

GnomAD2 exomes

AF:

0.731

AC:

182618

AN:

249766

AF XY:

0.728

show subpopulations

Gnomad AFR exome

AF:

0.953

Gnomad AMR exome

AF:

0.759

Gnomad ASJ exome

AF:

0.704

Gnomad EAS exome

AF:

0.551

Gnomad FIN exome

AF:

0.640

Gnomad NFE exome

AF:

0.740

Gnomad OTH exome

AF:

0.741

GnomAD4 exome

AF:

0.741

AC:

1082809

AN:

1461482

Hom.:

403068

Cov.:

AF XY:

0.740

AC XY:

537731

AN XY:

727014

show subpopulations

African (AFR)

AF:

0.953

AC:

31905

AN:

33480

American (AMR)

AF:

0.758

AC:

33896

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.706

AC:

18464

AN:

26136

East Asian (EAS)

AF:

0.566

AC:

22462

AN:

39700

South Asian (SAS)

AF:

0.732

AC:

63120

AN:

86258

European-Finnish (FIN)

AF:

0.647

AC:

34338

AN:

53088

Middle Eastern (MID)

AF:

0.718

AC:

4142

AN:

5766

European-Non Finnish (NFE)

AF:

0.746

AC:

829794

AN:

1111944

Other (OTH)

AF:

0.740

AC:

44688

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

17303

34606

51908

69211

86514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20264

40528

60792

81056

101320

<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:

0.785

AC:

119435

AN:

152092

Hom.:

47935

Cov.:

AF XY:

0.778

AC XY:

57826

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.949

AC:

39424

AN:

41536

American (AMR)

AF:

0.756

AC:

11565

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.701

AC:

2434

AN:

3472

East Asian (EAS)

AF:

0.549

AC:

2825

AN:

5150

South Asian (SAS)

AF:

0.708

AC:

3410

AN:

4814

European-Finnish (FIN)

AF:

0.638

AC:

6728

AN:

10550

Middle Eastern (MID)

AF:

0.714

AC:

210

AN:

294

European-Non Finnish (NFE)

AF:

0.742

AC:

50451

AN:

67968

Other (OTH)

AF:

0.772

AC:

1627

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1246

2492

3739

4985

6231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

860

1720

2580

3440

4300

<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:

0.769

Hom.:

30874

Bravo

AF:

0.803

Asia WGS

AF:

0.654

AC:

2275

AN:

3478

EpiCase

AF:

0.739

EpiControl

AF:

0.745

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Multiple endocrine neoplasia, type 2 (3)

not specified (3)

not provided (2)

Hereditary cancer-predisposing syndrome (1)

Hirschsprung disease, susceptibility to, 1 (1)

Multiple endocrine neoplasia type 2A (1)

Multiple endocrine neoplasia type 2B (1)

Pheochromocytoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.024

(source)

DANN

Benign

0.31

PhyloP100

-2.2

PromoterAI

-0.0084

Neutral

(source)

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over