rs759046760

Variant names:

• chr5-56815588-G-A
• rs759046760
• NM_005921.2:c.15G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-56815588-G-A
• chr5-56815588-G-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_005921.2(MAP3K1):​c.15G>A​(p.Ala5Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,296,296 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: MAP3K1 NM_005921.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.27
• Publications: 9 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

ENSG00000297204 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 5-56815588-G-A is Benign according to our data. Variant chr5-56815588-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1612863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.27 with no splicing effect.
• BS2: High AC in GnomAd4 at 383 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.15G>A	p.Ala5Ala	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.15G>A	p.Ala5Ala	synonymous	Exon 1 of 20	ENSP00000382423.3	Q13233
	MAP3K1	ENST00000872825.1		c.15G>A	p.Ala5Ala	synonymous	Exon 1 of 20	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.15G>A	p.Ala5Ala	synonymous	Exon 1 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 383 AN: 150850 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.0247

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.00141 AC: 11 AN: 7816 AF XY: 0.00140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00165 AC: 1889 AN: 1145334 Hom.: 4 Cov.: 31 AF XY: 0.00165 AC XY: 914 AN XY: 553586

African (AFR) AF: 0.000215 AC: 5 AN: 23208

American (AMR) AF: 0.000100 AC: 1 AN: 9970

Ashkenazi Jewish (ASJ) AF: 0.000579 AC: 9 AN: 15550

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

South Asian (SAS) AF: 0.000842 AC: 33 AN: 39200

European-Finnish (FIN) AF: 0.0177 AC: 426 AN: 24108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3124

European-Non Finnish (NFE) AF: 0.00142 AC: 1357 AN: 957492

Other (OTH) AF: 0.00127 AC: 58 AN: 45832

GnomAD4 genome AF: 0.00254 AC: 383 AN: 150962 Hom.: 9 Cov.: 33 AF XY: 0.00320 AC XY: 236 AN XY: 73778

African (AFR) AF: 0.000316 AC: 13 AN: 41166

American (AMR) AF: 0.000198 AC: 3 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5062

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4798

European-Finnish (FIN) AF: 0.0247 AC: 256 AN: 10382

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

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 67622

Other (OTH) AF: 0.00143 AC: 3 AN: 2096

Alfa AF: 0.000954 Hom.: 0

Bravo AF: 0.000608

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	46,XY sex reversal 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Uncertain	0.98
PhyloP100		2.3
PromoterAI		0.10	Neutral
Mutation Taster		=100/0	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: rs759046760; hg19: chr5-56111415;