rs376808920

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005921.2(MAP3K1):c.934A>T(p.Met312Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,614,038 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 4 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 2 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 8.03

Variant links:

Genes affected

MAP3K1 (HGNC:6848): (mitogen-activated protein kinase kinase kinase 1) The protein encoded by this gene is a serine/threonine kinase and is part of some signal transduction cascades, including the ERK and JNK kinase pathways as well as the NF-kappa-B pathway. The encoded protein is activated by autophosphorylation and requires magnesium as a cofactor in phosphorylating other proteins. This protein has E3 ligase activity conferred by a plant homeodomain (PHD) in its N-terminus and phospho-kinase activity conferred by a kinase domain in its C-terminus. [provided by RefSeq, Mar 2012]

MAP3K1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2 link	c.934A>T	p.Met312Leu	missense_variant	Exon 4 of 20	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 link	c.934A>T	p.Met312Leu	missense_variant	Exon 4 of 18		XP_047273174.1
MAP3K1	XM_047417219.1 link	c.523A>T	p.Met175Leu	missense_variant	Exon 5 of 21		XP_047273175.1
MAP3K1	XM_047417220.1 link	c.523A>T	p.Met175Leu	missense_variant	Exon 5 of 21		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4 link	c.934A>T	p.Met312Leu	missense_variant	Exon 4 of 20	1	NM_005921.2	ENSP00000382423.3		Q13233

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.0000561

AC:

AN:

249368

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135286

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000390

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.0000944

AC:

138

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000453

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00177

GnomAD4 genome

AF:

0.000197

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000955

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000151

ExAC

AF:

0.0000745

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

46,XY sex reversal 6

Uncertain:2Benign:1

Jan 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with 46,XY sex reversal 6 (MIM#613762). Functional studies of missense variants observed in affected individuals have shown they increase phosphorylation of downstream products causing increased activation of the MAPK pathway (PMIDs: 24135036, 21129722, 30608580). (I) 0107 - This gene is associated with autosomal dominant disease. The condition associated with this gene is inherited in a sex limited manner; only individuals with a 46,XY karyotype are affected (PMID: 20301714). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial and interfamilial variability have been reported, with individuals harbouring the same variants observed to have variable phenotypes, ranging from hypospadias to complete gonadal dysgenesis (PMIDs: 27899157, 12476449, 21129722). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to leucine. (I) 0251 - This variant is heterozygous. (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0310 - Variant is present in gnomAD (v3) >=0.001 and <0.01 for a dominant condition (22 heterozygotes, 4 homozygotes). However, the four homozygotes and 17 heterozygotes had an XX karyotype and would therefore be expected to be unaffected carriers of 46,XY sex reversal. (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic in four individuals in the literature with variable phenotypes including hypospadias, disorders of sex development, and complete gonadal dysgenesis (PMID: 27899157). However, two of these individuals also had a variant in another gene associated with DSD. This variant has also been classified as likely pathogenic, likely benign and as a VUS by clinical laboratories in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not specified

Uncertain:1

Mar 31, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.065

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.1

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.21

REVEL

Benign

0.25

Sift

Benign

0.29

Sift4G

Benign

0.77

Polyphen

0.73

Vest4

0.81

MutPred

0.29

Gain of ubiquitination at K310 (P = 0.0514);

MVP

0.81

MPC

0.23

ClinPred

0.14

GERP RS

5.6

Varity_R

0.33

gMVP

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over