3-9473449-A-G

Position:

• chr3-9473449-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0075 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (14 hom.)
• Consequence: SETD5 NM_001080517.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.16

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1147 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD5	NM_001080517.3	c.3409A>G	p.Met1137Val	missense_variant	20/23	ENST00000402198.7	NP_001073986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD5	ENST00000402198.7	c.3409A>G	p.Met1137Val	missense_variant	20/23	5	NM_001080517.3	ENSP00000385852	P4

Frequencies

GnomAD3 genomes AF: 0.00753 AC: 1145 AN: 152036 Hom.: 20 Cov.: 32

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

GnomAD3 exomes AF: 0.00202 AC: 502 AN: 249076 Hom.: 6 AF XY: 0.00157 AC XY: 212 AN XY: 135124

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 SAS exome AF: 0.0000327

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.: 14 Cov.: 33 AF XY: 0.000814 AC XY: 592 AN XY: 727108

Gnomad4 AFR exome AF: 0.0227

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000297

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.00754 AC: 1147 AN: 152152 Hom.: 20 Cov.: 32 AF XY: 0.00707 AC XY: 526 AN XY: 74400

Gnomad4 AFR AF: 0.0244

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00151 Hom.: 4

Bravo AF: 0.00878

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0191 AC: 73

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.00218 AC: 264

Asia WGS AF: 0.000866 AC: 3 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

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.51
DANN	Benign	0.57
DEOGEN2	Benign	0.0095	T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.80	T;.;T;T
MetaRNN	Benign	0.0015	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.040	N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.82	T;T;T;T
Sift4G	Benign	0.55	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.085
MVP		0.30
MPC		0.082
ClinPred		0.0050	T
GERP RS		-9.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs13327456; hg19: chr3-9515133; COSMIC: COSV56708070; COSMIC: COSV56708070;