5-56815618-G-A

Variant names:

• chr5-56815618-G-A
• rs192120973
• NM_005921.2:c.45G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005921.2(MAP3K1):​c.45G>A​(p.Pro15Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,311,048 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (105 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (79 hom.)
• Consequence: MAP3K1 NM_005921.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.78
• Publications: 1 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 5-56815618-G-A is Benign according to our data. Variant chr5-56815618-G-A is described in ClinVar as Benign. ClinVar VariationId is 1168726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0712 is higher than 0.05.

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.45G>A	p.Pro15Pro	synonymous	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.45G>A	p.Pro15Pro	synonymous	Exon 1 of 20	ENSP00000382423.3	Q13233
	MAP3K1	ENST00000872825.1		c.45G>A	p.Pro15Pro	synonymous	Exon 1 of 20	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.45G>A	p.Pro15Pro	synonymous	Exon 1 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3134 AN: 151016 Hom.: 103 Cov.: 33

Gnomad AFR AF: 0.0731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00579

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.0135

GnomAD2 exomes AF: 0.00207 AC: 46 AN: 22208 AF XY: 0.00122

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.00441

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00172 AC: 1995 AN: 1159920 Hom.: 79 Cov.: 31 AF XY: 0.00151 AC XY: 849 AN XY: 562730

African (AFR) AF: 0.0731 AC: 1717 AN: 23492

American (AMR) AF: 0.00381 AC: 46 AN: 12072

Ashkenazi Jewish (ASJ) AF: 0.0000591 AC: 1 AN: 16922

East Asian (EAS) AF: 0.00 AC: 0 AN: 26846

South Asian (SAS) AF: 0.000210 AC: 9 AN: 42844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24758

Middle Eastern (MID) AF: 0.00188 AC: 6 AN: 3198

European-Non Finnish (NFE) AF: 0.0000363 AC: 35 AN: 963428

Other (OTH) AF: 0.00390 AC: 181 AN: 46360

GnomAD4 genome AF: 0.0209 AC: 3152 AN: 151128 Hom.: 105 Cov.: 33 AF XY: 0.0193 AC XY: 1425 AN XY: 73858

African (AFR) AF: 0.0734 AC: 3027 AN: 41248

American (AMR) AF: 0.00572 AC: 87 AN: 15218

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67644

Other (OTH) AF: 0.0133 AC: 28 AN: 2098

Alfa AF: 0.0198 Hom.: 9

Bravo AF: 0.0230

Asia WGS AF: 0.00439 AC: 15 AN: 3430

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	46,XY sex reversal 6 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.97
PhyloP100		2.8
PromoterAI		0.0042	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs192120973; hg19: chr5-56111445;