NM_032435.3:c.1790C>T

Variant names:

• chr1-233376030-C-T
• rs34984140
• NM_032435.3:c.1790C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_032435.3(MAP3K21):​c.1790C>T​(p.Ser597Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 1,608,574 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (6 hom.)
• Consequence: MAP3K21 NM_032435.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.49
• Publications: 10 publications found

Genes affected

MAP3K21 (HGNC:29798): (mitogen-activated protein kinase kinase kinase 21) Predicted to enable protein homodimerization activity and protein kinase activity. Predicted to be involved in protein autophosphorylation and signal transduction. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027572572).
• BP6: Variant 1-233376030-C-T is Benign according to our data. Variant chr1-233376030-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2640090.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032435.3. 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
	MAP3K21	NM_032435.3	MANE Select	c.1790C>T	p.Ser597Phe	missense	Exon 7 of 10	NP_115811.2	Q5TCX8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K21	ENST00000366624.8	TSL:1 MANE Select	c.1790C>T	p.Ser597Phe	missense	Exon 7 of 10	ENSP00000355583.3	Q5TCX8-1
	MAP3K21	ENST00000366622.1	TSL:1	c.128C>T	p.Ser43Phe	missense	Exon 1 of 4	ENSP00000355581.1	Q5TCX8-3
	MAP3K21	ENST00000915953.1		c.1790C>T	p.Ser597Phe	missense	Exon 7 of 10	ENSP00000586012.1

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00246 AC: 603 AN: 245202 AF XY: 0.00253

Gnomad AFR exome AF: 0.000573

Gnomad AMR exome AF: 0.00103

Gnomad ASJ exome AF: 0.00391

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00477

Gnomad NFE exome AF: 0.00354

Gnomad OTH exome AF: 0.00335

GnomAD4 exome AF: 0.00266 AC: 3870 AN: 1456292 Hom.: 6 Cov.: 30 AF XY: 0.00264 AC XY: 1916 AN XY: 724388

African (AFR) AF: 0.000424 AC: 14 AN: 32998

American (AMR) AF: 0.00111 AC: 48 AN: 43130

Ashkenazi Jewish (ASJ) AF: 0.00580 AC: 151 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.0000590 AC: 5 AN: 84786

European-Finnish (FIN) AF: 0.00543 AC: 290 AN: 53378

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5750

European-Non Finnish (NFE) AF: 0.00285 AC: 3166 AN: 1110526

Other (OTH) AF: 0.00316 AC: 190 AN: 60164

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74458

African (AFR) AF: 0.000553 AC: 23 AN: 41562

American (AMR) AF: 0.00262 AC: 40 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

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

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00509 AC: 54 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00316 AC: 215 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00281 Hom.: 1

Bravo AF: 0.00209

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00268 AC: 23

ExAC AF: 0.00255 AC: 310

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00440

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-1.1	T
PhyloP100		7.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.87
MVP		0.53
MPC		0.55
ClinPred		0.030	T
GERP RS		5.3
PromoterAI		0.017	Neutral
Varity_R		0.76
gMVP		0.65
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34984140; hg19: chr1-233511776;