5-56815608-C-T

Variant names:

• chr5-56815608-C-T
• rs2111725063
• NM_005921.2:c.35C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005921.2(MAP3K1):​c.35C>T​(p.Ser12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000173 in 1,158,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S12P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.139
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• 46,XY sex reversal 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• breast cancer

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• 46,XY complete gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000297204 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13847274).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005921.2. 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
	MAP3K1	NM_005921.2	MANE Select	c.35C>T	p.Ser12Leu	missense	Exon 1 of 20	NP_005912.1	Q13233

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	ENST00000399503.4	TSL:1 MANE Select	c.35C>T	p.Ser12Leu	missense	Exon 1 of 20	ENSP00000382423.3	Q13233
	MAP3K1	ENST00000872825.1		c.35C>T	p.Ser12Leu	missense	Exon 1 of 20	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.35C>T	p.Ser12Leu	missense	Exon 1 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000173 AC: 2 AN: 1158214 Hom.: 0 Cov.: 31 AF XY: 0.00000178 AC XY: 1 AN XY: 561332

African (AFR) AF: 0.00 AC: 0 AN: 23552

American (AMR) AF: 0.000164 AC: 2 AN: 12170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16754

East Asian (EAS) AF: 0.00 AC: 0 AN: 26850

South Asian (SAS) AF: 0.00 AC: 0 AN: 42536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 962120

Other (OTH) AF: 0.00 AC: 0 AN: 46342

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.14
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.033
Sift	Benign	0.30	T
Sift4G	Benign	0.16	T
Polyphen		0.0020	B
Vest4		0.17
MutPred		0.20		Loss of glycosylation at S12 (P = 1e-04)
MVP		0.50
MPC		0.20
ClinPred		0.26	T
GERP RS		2.1
PromoterAI		-0.025	Neutral
Varity_R		0.12
gMVP		0.15
Mutation Taster		=92/8	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: rs2111725063; hg19: chr5-56111435;