Genetic Variant NM_016848.6:c.1338A>G (chr9-89042048-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_016848.6(SHC3):c.1338A>G(p.Pro446Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 1,613,176 control chromosomes in the GnomAD database, including 372,464 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 0.71 ( 38494 hom., cov: 33)

Exomes 𝑓: 0.67 ( 333970 hom. )

Consequence

SHC3
NM_016848.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.31

Publications

16 publications found

Variant links:

Genes affected

SHC3 (HGNC:18181): (SHC adaptor protein 3) Enables phosphotyrosine residue binding activity. Predicted to be involved in transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to act upstream of or within glutamatergic synaptic transmission and learning or memory. Predicted to be located in cytosol. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SHC3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP7

Synonymous conserved (PhyloP=-2.31 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHC3	NM_016848.6 link	c.1338A>G	p.Pro446Pro	synonymous_variant	Exon 10 of 12	ENST00000375835.9	NP_058544.3	Q92529-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHC3	ENST00000375835.9 link	c.1338A>G	p.Pro446Pro	synonymous_variant	Exon 10 of 12	1	NM_016848.6	ENSP00000364995.4		Q92529-1
SHC3	ENST00000375831.1 link	c.-19A>G		5_prime_UTR_variant	Exon 1 of 3	2		ENSP00000364991.1		Q5T7I8

Frequencies

GnomAD3 genomes

AF:

0.706

AC:

107424

AN:

152058

Hom.:

38456

Cov.:

show subpopulations

Gnomad AFR

AF:

0.770

Gnomad AMI

AF:

0.467

Gnomad AMR

AF:

0.729

Gnomad ASJ

AF:

0.705

Gnomad EAS

AF:

0.987

Gnomad SAS

AF:

0.721

Gnomad FIN

AF:

0.655

Gnomad MID

AF:

0.620

Gnomad NFE

AF:

0.652

Gnomad OTH

AF:

0.705

GnomAD2 exomes

AF:

0.714

AC:

178783

AN:

250540

AF XY:

0.706

show subpopulations

Gnomad AFR exome

AF:

0.771

Gnomad AMR exome

AF:

0.799

Gnomad ASJ exome

AF:

0.713

Gnomad EAS exome

AF:

0.988

Gnomad FIN exome

AF:

0.653

Gnomad NFE exome

AF:

0.649

Gnomad OTH exome

AF:

0.691

GnomAD4 exome

AF:

0.672

AC:

982278

AN:

1460998

Hom.:

333970

Cov.:

AF XY:

0.671

AC XY:

488022

AN XY:

726844

show subpopulations

African (AFR)

AF:

0.770

AC:

25691

AN:

33366

American (AMR)

AF:

0.795

AC:

35374

AN:

44512

Ashkenazi Jewish (ASJ)

AF:

0.712

AC:

18584

AN:

26098

East Asian (EAS)

AF:

0.985

AC:

39100

AN:

39690

South Asian (SAS)

AF:

0.702

AC:

60437

AN:

86110

European-Finnish (FIN)

AF:

0.654

AC:

34861

AN:

53314

Middle Eastern (MID)

AF:

0.591

AC:

3409

AN:

5764

European-Non Finnish (NFE)

AF:

0.651

AC:

723225

AN:

1111794

Other (OTH)

AF:

0.689

AC:

41597

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

17602

35204

52807

70409

88011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19112

38224

57336

76448

95560

<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:

0.707

AC:

107521

AN:

152178

Hom.:

38494

Cov.:

AF XY:

0.709

AC XY:

52751

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.770

AC:

31976

AN:

41516

American (AMR)

AF:

0.730

AC:

11164

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.705

AC:

2448

AN:

3472

East Asian (EAS)

AF:

0.987

AC:

5098

AN:

5164

South Asian (SAS)

AF:

0.720

AC:

3478

AN:

4830

European-Finnish (FIN)

AF:

0.655

AC:

6941

AN:

10596

Middle Eastern (MID)

AF:

0.612

AC:

180

AN:

294

European-Non Finnish (NFE)

AF:

0.652

AC:

44316

AN:

67988

Other (OTH)

AF:

0.707

AC:

1497

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1612

3225

4837

6450

8062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

826

1652

2478

3304

4130

<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.:

147357

Bravo

AF:

0.717

Asia WGS

AF:

0.867

AC:

3017

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.013

(source)

DANN

Benign

0.62

PhyloP100

-2.3

PromoterAI

0.015

Neutral

(source)

Mutation Taster

=300/0

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