NM_004119.3:c.2962G>C

Variant names:

• chr13-28004072-C-G
• rs74041526
• NM_004119.3:c.2962G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004119.3(FLT3):​c.2962G>C​(p.Ala988Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,614,070 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (22 hom.)
• Consequence: FLT3 NM_004119.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.0720
• Publications: 12 publications found

Genes affected

FLT3 (HGNC:3765): (fms related receptor tyrosine kinase 3) This gene encodes a class III receptor tyrosine kinase that regulates hematopoiesis. This receptor is activated by binding of the fms-related tyrosine kinase 3 ligand to the extracellular domain, which induces homodimer formation in the plasma membrane leading to autophosphorylation of the receptor. The activated receptor kinase subsequently phosphorylates and activates multiple cytoplasmic effector molecules in pathways involved in apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. Mutations that result in the constitutive activation of this receptor result in acute myeloid leukemia and acute lymphoblastic leukemia. [provided by RefSeq, Jan 2015]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031681657).
• BP6: Variant 13-28004072-C-G is Benign according to our data. Variant chr13-28004072-C-G is described in ClinVar as Benign. ClinVar VariationId is 134441.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 = 0.00819 (1247/152226) while in subpopulation AFR AF = 0.0285 (1184/41530). AF 95% confidence interval is 0.0272. There are 15 homozygotes in GnomAd4. There are 597 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1247 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004119.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT3	NM_004119.3	MANE Select	c.2962G>C	p.Ala988Pro	missense	Exon 24 of 24	NP_004110.2	P36888-1
	FLT3	NR_130706.2		n.3160G>C		non_coding_transcript_exon	Exon 25 of 25

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT3	ENST00000241453.12	TSL:1 MANE Select	c.2962G>C	p.Ala988Pro	missense	Exon 24 of 24	ENSP00000241453.7	P36888-1
	FLT3	ENST00000380987.2	TSL:1	n.*874G>C		non_coding_transcript_exon	Exon 25 of 25	ENSP00000370374.2	E7ER61
	FLT3	ENST00000380987.2	TSL:1	n.*874G>C		3_prime_UTR	Exon 25 of 25	ENSP00000370374.2	E7ER61

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 1238 AN: 152108 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00212 AC: 532 AN: 251488 AF XY: 0.00163

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000919 AC: 1343 AN: 1461844 Hom.: 22 Cov.: 31 AF XY: 0.000795 AC XY: 578 AN XY: 727220

African (AFR) AF: 0.0310 AC: 1038 AN: 33476

American (AMR) AF: 0.00116 AC: 52 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5752

European-Non Finnish (NFE) AF: 0.0000971 AC: 108 AN: 1112000

Other (OTH) AF: 0.00207 AC: 125 AN: 60390

GnomAD4 genome AF: 0.00819 AC: 1247 AN: 152226 Hom.: 15 Cov.: 32 AF XY: 0.00802 AC XY: 597 AN XY: 74436

African (AFR) AF: 0.0285 AC: 1184 AN: 41530

American (AMR) AF: 0.00229 AC: 35 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.000400 Hom.: 0

Bravo AF: 0.00915

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0293 AC: 129

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00275 AC: 334

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	3.7
DANN	Benign	0.92
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.072
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.16
Sift	Benign	0.037	D
Sift4G	Benign	0.28	T
Polyphen		0.17	B
Vest4		0.067
MVP		0.40
MPC		0.18
ClinPred		0.0018	T
GERP RS		1.6
Varity_R		0.059
gMVP		0.49
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs74041526; hg19: chr13-28578209;