5-56859707-T-A

Position:

• chr5-56859707-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_005921.2(MAP3K1):​c.634-8T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K1 NM_005921.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.652

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-56859707-T-A is Pathogenic according to our data. Variant chr5-56859707-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 30144.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-56859707-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K1	NM_005921.2	c.634-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000399503.4
MAP3K1	XM_047417218.1	c.634-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
MAP3K1	XM_047417219.1	c.223-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
MAP3K1	XM_047417220.1	c.223-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K1	ENST00000399503.4	c.634-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005921.2	P1
	ENST00000415589.1	n.298A>T		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

46,XY sex reversal 6 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with 46,XY sex reversal 6 (MIM#613762) (PMIDs: 21129722, 24135036, 30608580). (I) 0107 - This gene is associated with autosomal dominant disease. However, it is sex-limited in that only 46XY individuals are affected (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Intra- and inter-familial variability have been reported (PMIDs: 27899157, 12476449, 21129722). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA analysis from affected individuals demonstrated presence of an aberrant transcript containing an insertion of 6bp, predicted to result in p.(Val211_Val212insIleGln) (PMID: 21129722). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated GEF domain (PMID: 30608580). (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It has been identified in a large multi-generational French family (PMID: 21129722). (SP) 0901 - This variant has strong evidence for segregation with disease. Five heterozygous affected individuals were identified in a large multi-generational family. The other affecteds were not genotyped (PMID: 21129722). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 10, 2010	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	21
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.51		Position offset: 2
DS_AL_spliceai		0.88		Position offset: 8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1131692053; hg19: chr5-56155534;