Genetic Variant SETD5:p.Met1137Val (chr3-9473449-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001080517.3(SETD5):c.3409A>G(p.Met1137Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,613,814 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1137I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0075 ( 20 hom., cov: 32)

Exomes 𝑓: 0.00092 ( 14 hom. )

Consequence

SETD5
NM_001080517.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.16

Publications

5 publications found

Variant links:

Genes affected

SETD5 (HGNC:25566): (SET domain containing 5) This function of this gene has yet to be determined but based on sequence similarity to other SET domain proteins it may function as a histone methyltransferase. Mutations in this gene have been associated with an autosomal dominant form of intellectual disability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

SETD5 Gene-Disease associations (from GenCC):

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
syndromic complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

SETD5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0015499294).

BP6

Variant 3-9473449-A-G is Benign according to our data. Variant chr3-9473449-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00754 (1147/152152) while in subpopulation AFR AF = 0.0244 (1013/41502). AF 95% confidence interval is 0.0232. There are 20 homozygotes in GnomAd4. There are 526 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1147 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080517.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SETD5	NM_001080517.3	MANE Select	c.3409A>G	p.Met1137Val	missense	Exon 20 of 23	NP_001073986.1
SETD5	NM_001437635.1		c.3523A>G	p.Met1175Val	missense	Exon 21 of 24	NP_001424564.1
SETD5	NM_001437633.1		c.3505A>G	p.Met1169Val	missense	Exon 21 of 24	NP_001424562.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SETD5	ENST00000402198.7	TSL:5 MANE Select	c.3409A>G	p.Met1137Val	missense	Exon 20 of 23	ENSP00000385852.2
SETD5	ENST00000493918.5	TSL:1	n.3573A>G		non_coding_transcript_exon	Exon 16 of 19
SETD5	ENST00000682536.1		c.3505A>G	p.Met1169Val	missense	Exon 21 of 24	ENSP00000507956.1

Frequencies

GnomAD3 genomes

AF:

0.00753

AC:

1145

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00814

GnomAD2 exomes

AF:

0.00202

AC:

502

AN:

249076

AF XY:

0.00157

show subpopulations

Gnomad AFR exome

AF:

0.0250

Gnomad AMR exome

AF:

0.00189

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000354

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000924

AC:

1350

AN:

1461662

Hom.:

Cov.:

AF XY:

0.000814

AC XY:

592

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.0227

AC:

760

AN:

33480

American (AMR)

AF:

0.00228

AC:

102

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000297

AC:

330

AN:

1111848

Other (OTH)

AF:

0.00220

AC:

133

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

174

260

347

434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00754

AC:

1147

AN:

152152

Hom.:

Cov.:

AF XY:

0.00707

AC XY:

526

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0244

AC:

1013

AN:

41502

American (AMR)

AF:

0.00556

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

67990

Other (OTH)

AF:

0.00806

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

126

190

253

316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00276

Hom.:

Bravo

AF:

0.00878

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0191

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.00218

AC:

264

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

May 03, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 15, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.51

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.0095

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

PhyloP100

-1.2

PrimateAI

Benign

0.24

PROVEAN

Benign

0.040

REVEL

Uncertain

0.33

Sift

Benign

0.82

Sift4G

Benign

0.55

Polyphen

0.0

Vest4

0.085

MVP

0.30

MPC

0.082

ClinPred

0.0050

GERP RS

-9.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.023

gMVP

0.13

Mutation Taster

=98/2

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over