rs726501

Variant names:

• chr5-56832039-G-A
• rs726501
• NM_005921.2:c.482+15984G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005921.2(MAP3K1):​c.482+15984G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0985 in 152,168 control chromosomes in the GnomAD database, including 1,184 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.098 (1184 hom., cov: 32)
• Consequence: MAP3K1 NM_005921.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• 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, 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2	c.482+15984G>A		intron_variant	Intron 1 of 19	ENST00000399503.4	NP_005912.1
MAP3K1	XM_047417218.1	c.482+15984G>A		intron_variant	Intron 1 of 17		XP_047273174.1
MAP3K1	XM_047417219.1	c.71+11223G>A		intron_variant	Intron 2 of 20		XP_047273175.1
MAP3K1	XM_047417220.1	c.71+11223G>A		intron_variant	Intron 2 of 20		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4	c.482+15984G>A		intron_variant	Intron 1 of 19	1	NM_005921.2	ENSP00000382423.3

Frequencies

GnomAD3 genomes AF: 0.0984 AC: 14960 AN: 152050 Hom.: 1174 Cov.: 32

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.0824

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0974

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.0881

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0994

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0985 AC: 14987 AN: 152168 Hom.: 1184 Cov.: 32 AF XY: 0.105 AC XY: 7795 AN XY: 74404

African (AFR) AF: 0.0215 AC: 892 AN: 41540

American (AMR) AF: 0.154 AC: 2348 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0974 AC: 338 AN: 3470

East Asian (EAS) AF: 0.327 AC: 1688 AN: 5168

South Asian (SAS) AF: 0.285 AC: 1375 AN: 4822

European-Finnish (FIN) AF: 0.0881 AC: 932 AN: 10584

Middle Eastern (MID) AF: 0.120 AC: 35 AN: 292

European-Non Finnish (NFE) AF: 0.104 AC: 7081 AN: 67988

Other (OTH) AF: 0.105 AC: 223 AN: 2114

Alfa AF: 0.104 Hom.: 3171

Bravo AF: 0.0977

Asia WGS AF: 0.301 AC: 1043 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.37
DANN	Benign	0.38
PhyloP100		-1.1
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: rs726501; hg19: chr5-56127866;