5-56815654-C-T

Variant names:

• chr5-56815654-C-T
• rs185050655
• NM_005921.2:c.81C>T

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.81C>T​(p.Gly27Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00476 in 1,333,836 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (51 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (89 hom.)
• Consequence: MAP3K1 NM_005921.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00300
• 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, 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 5-56815654-C-T is Benign according to our data. Variant chr5-56815654-C-T is described in ClinVar as Benign. ClinVar VariationId is 471696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.003 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0562 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.81C>T	p.Gly27Gly	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.81C>T	p.Gly27Gly	synonymous	Exon 1 of 20	ENSP00000382423.3	Q13233
	MAP3K1	ENST00000872825.1		c.81C>T	p.Gly27Gly	synonymous	Exon 1 of 20	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.81C>T	p.Gly27Gly	synonymous	Exon 1 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes AF: 0.00799 AC: 1210 AN: 151434 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.00189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0593

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0177 AC: 674 AN: 38058 AF XY: 0.0123

Gnomad AFR exome AF: 0.00186

Gnomad AMR exome AF: 0.0970

Gnomad ASJ exome AF: 0.000829

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00258

Gnomad OTH exome AF: 0.00924

GnomAD4 exome AF: 0.00434 AC: 5134 AN: 1182294 Hom.: 89 Cov.: 32 AF XY: 0.00409 AC XY: 2355 AN XY: 575676

African (AFR) AF: 0.00161 AC: 39 AN: 24268

American (AMR) AF: 0.0965 AC: 1510 AN: 15644

Ashkenazi Jewish (ASJ) AF: 0.000164 AC: 3 AN: 18296

East Asian (EAS) AF: 0.00 AC: 0 AN: 26876

South Asian (SAS) AF: 0.0000429 AC: 2 AN: 46640

European-Finnish (FIN) AF: 0.000235 AC: 6 AN: 25542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3322

European-Non Finnish (NFE) AF: 0.00342 AC: 3336 AN: 974188

Other (OTH) AF: 0.00501 AC: 238 AN: 47518

GnomAD4 genome AF: 0.00800 AC: 1213 AN: 151542 Hom.: 51 Cov.: 33 AF XY: 0.00856 AC XY: 634 AN XY: 74058

African (AFR) AF: 0.00188 AC: 78 AN: 41436

American (AMR) AF: 0.0594 AC: 905 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00297 AC: 201 AN: 67780

Other (OTH) AF: 0.0133 AC: 28 AN: 2104

Alfa AF: 0.00589 Hom.: 0

Bravo AF: 0.0139

ClinVar

ClinVar submissions

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	-0.38
CADD	Benign	14
DANN	Benign	0.95
PhyloP100		-0.0030
PromoterAI		0.0082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
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: rs185050655; hg19: chr5-56111481;