5-56815734-G-C

Variant names:

• chr5-56815734-G-C
• rs1050828981
• NM_005921.2:c.161G>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.161G>C​(p.Arg54Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,347,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R54Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52
• 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, Labcorp Genetics (formerly Invitae), G2P
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3635865).
• BS2: High AC in GnomAdExome4 at 16 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.161G>C	p.Arg54Pro	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.161G>C	p.Arg54Pro	missense	Exon 1 of 20	ENSP00000382423.3	Q13233
	MAP3K1	ENST00000872825.1		c.161G>C	p.Arg54Pro	missense	Exon 1 of 20	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.161G>C	p.Arg54Pro	missense	Exon 1 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150722 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000134 AC: 16 AN: 1197168 Hom.: 0 Cov.: 31 AF XY: 0.0000222 AC XY: 13 AN XY: 584416

African (AFR) AF: 0.00 AC: 0 AN: 25054

American (AMR) AF: 0.00 AC: 0 AN: 19748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19398

East Asian (EAS) AF: 0.00 AC: 0 AN: 26318

South Asian (SAS) AF: 0.00 AC: 0 AN: 47530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3474

European-Non Finnish (NFE) AF: 0.0000153 AC: 15 AN: 980538

Other (OTH) AF: 0.0000207 AC: 1 AN: 48356

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150722 Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 1 AN XY: 73560

African (AFR) AF: 0.00 AC: 0 AN: 41170

American (AMR) AF: 0.0000660 AC: 1 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67532

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	T
Eigen	Benign	0.090
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.25
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.098	T
Polyphen		0.98	D
Vest4		0.34
MutPred		0.15		Gain of glycosylation at R54 (P = 0.0443)
MVP		0.60
MPC		0.60
ClinPred		0.63	D
GERP RS		2.8
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.12
Mutation Taster		=66/34	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: rs1050828981; hg19: chr5-56111561;