5-56815586-G-C

Variant names:

• chr5-56815586-G-C
• NM_005921.2:c.13G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005921.2(MAP3K1):​c.13G>C​(p.Ala5Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000061 in 1,147,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A5A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000061 (0 hom.)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.50
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.315155).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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.13G>C	p.Ala5Pro	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.13G>C	p.Ala5Pro	missense	Exon 1 of 20	ENSP00000382423.3	Q13233
	MAP3K1	ENST00000872825.1		c.13G>C	p.Ala5Pro	missense	Exon 1 of 20	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.13G>C	p.Ala5Pro	missense	Exon 1 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000610 AC: 7 AN: 1147348 Hom.: 0 Cov.: 31 AF XY: 0.00000721 AC XY: 4 AN XY: 554770

African (AFR) AF: 0.00 AC: 0 AN: 23226

American (AMR) AF: 0.00 AC: 0 AN: 9966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15550

East Asian (EAS) AF: 0.00 AC: 0 AN: 26884

South Asian (SAS) AF: 0.00 AC: 0 AN: 39504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3130

European-Non Finnish (NFE) AF: 0.00000730 AC: 7 AN: 958908

Other (OTH) AF: 0.00 AC: 0 AN: 45948

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	46,XY sex reversal 6 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	T
Eigen	Benign	0.091
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.026	D
Polyphen		0.77	P
Vest4		0.25
MutPred		0.24		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.64
MPC		0.30
ClinPred		0.70	D
GERP RS		3.9
PromoterAI		-0.014	Neutral
Varity_R		0.49
gMVP		0.20
Mutation Taster		=69/31	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

hg19: chr5-56111413;