4-153358621-A-G

Variant names:

• chr4-153358621-A-G
• rs1442950829
• NM_032117.4:c.275A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032117.4(MND1):​c.275A>G​(p.Gln92Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MND1 NM_032117.4 missense, splice_region
• Scores: Splicing: ADA: 0.9774
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.81

Genes affected

MND1 (HGNC:24839): (meiotic nuclear divisions 1) The product of the MND1 gene associates with HOP2 (MIM 608665) to form a stable heterodimeric complex that binds DNA and stimulates the recombinase activity of RAD51 (MIM 179617) and DMC1 (MIM 602721) (Chi et al., 2007 [PubMed 17639080]). Both the MND1 and HOP2 genes are indispensable for meiotic recombination.[supplied by OMIM, Mar 2008]

ENSG00000288637 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MND1	NM_032117.4	c.275A>G	p.Gln92Arg	missense_variant, splice_region_variant	Exon 4 of 8	ENST00000240488.8	NP_115493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MND1	ENST00000240488.8	c.275A>G	p.Gln92Arg	missense_variant, splice_region_variant	Exon 4 of 8	1	NM_032117.4	ENSP00000240488.3
ENSG00000288637	ENST00000675079.1	c.2366A>G	p.Gln789Arg	missense_variant, splice_region_variant	Exon 14 of 18			ENSP00000502677.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459168 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725842

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.275A>G (p.Q92R) alteration is located in exon 4 (coding exon 4) of the MND1 gene. This alteration results from a A to G substitution at nucleotide position 275, causing the glutamine (Q) at amino acid position 92 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T;T;T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.0096	T
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.6	.;M;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.5	.;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.20	.;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.0090	.;B;.;.
Vest4		0.71
MutPred		0.53		Gain of MoRF binding (P = 0.0346);Gain of MoRF binding (P = 0.0346);.;.;
MVP		0.28
MPC		0.099
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.26
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1442950829; hg19: chr4-154279773;