rs376808920

Positions:

• chr5-56864833-A-T

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 8.03

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]

ACMG classification

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/exons	MANE	Protein	UniProt
MAP3K1	NM_005921.2	c.934A>T	p.Met312Leu	missense_variant	4/20	ENST00000399503.4	NP_005912.1
MAP3K1	XM_047417218.1	c.934A>T	p.Met312Leu	missense_variant	4/18		XP_047273174.1
MAP3K1	XM_047417219.1	c.523A>T	p.Met175Leu	missense_variant	5/21		XP_047273175.1
MAP3K1	XM_047417220.1	c.523A>T	p.Met175Leu	missense_variant	5/21		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4	c.934A>T	p.Met312Leu	missense_variant	4/20	1	NM_005921.2	ENSP00000382423.3

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152166 Hom.: 4 Cov.: 32

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: 14 AN: 249368 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135286

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.: 2 Cov.: 32 AF XY: 0.0000825 AC XY: 60 AN XY: 727244

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: 30 AN: 152166 Hom.: 4 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74330

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.: 0

Bravo AF: 0.000151

ExAC AF: 0.0000745 AC: 9

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

46,XY sex reversal 6 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 03, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 29, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	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

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 31, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	L
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.25
Sift	Benign	0.29	T
Sift4G	Benign	0.77	T
Polyphen		0.73	P
Vest4		0.81
MutPred		0.29		Gain of ubiquitination at K310 (P = 0.0514);
MVP		0.81
MPC		0.23
ClinPred		0.14	T
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

Other links and lift over

dbSNP: rs376808920; hg19: chr5-56160660; COSMIC: COSV68123929; COSMIC: COSV68123929;