7-1936821-C-T

Variant names:

• chr7-1936821-C-T
• rs1801368
• NM_001013836.2:c.1673G>A

Variant summary

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

The NM_001013836.2(MAD1L1):​c.1673G>A​(p.Arg558His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,599,380 control chromosomes in the GnomAD database, including 112,418 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R558C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (7874 hom., cov: 34)
  • Exomes 𝑓: 0.37 (104544 hom.)
• Consequence: MAD1L1 NM_001013836.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.140
• Publications: 56 publications found

Genes affected

MAD1L1 (HGNC:6762): (mitotic arrest deficient 1 like 1) MAD1L1 is a component of the mitotic spindle-assembly checkpoint that prevents the onset of anaphase until all chromosome are properly aligned at the metaphase plate. MAD1L1 functions as a homodimer and interacts with MAD2L1. MAD1L1 may play a role in cell cycle control and tumor suppression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

MAD1L1 Gene-Disease associations (from GenCC):

• mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• familial prostate carcinoma

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000286192 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=2.9471517E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAD1L1	NM_001013836.2	c.1673G>A	p.Arg558His	missense_variant	Exon 17 of 19	ENST00000265854.12	NP_001013858.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAD1L1	ENST00000265854.12	c.1673G>A	p.Arg558His	missense_variant	Exon 17 of 19	1	NM_001013836.2	ENSP00000265854.7
ENSG00000286192	ENST00000651235.1	n.*4433G>A		non_coding_transcript_exon_variant	Exon 22 of 24			ENSP00000498895.1
ENSG00000286192	ENST00000651235.1	n.*4433G>A		3_prime_UTR_variant	Exon 22 of 24			ENSP00000498895.1

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44715 AN: 152114 Hom.: 7874 Cov.: 34

Gnomad AFR AF: 0.0919

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.331

GnomAD2 exomes AF: 0.352 AC: 78399 AN: 222486 AF XY: 0.350

Gnomad AFR exome AF: 0.0791

Gnomad AMR exome AF: 0.449

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.476

Gnomad FIN exome AF: 0.299

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.348

GnomAD4 exome AF: 0.374 AC: 541485 AN: 1447148 Hom.: 104544 Cov.: 62 AF XY: 0.373 AC XY: 267884 AN XY: 718536

African (AFR) AF: 0.0747 AC: 2493 AN: 33356

American (AMR) AF: 0.444 AC: 18851 AN: 42496

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 7866 AN: 25818

East Asian (EAS) AF: 0.448 AC: 17506 AN: 39056

South Asian (SAS) AF: 0.329 AC: 27568 AN: 83766

European-Finnish (FIN) AF: 0.307 AC: 15789 AN: 51422

Middle Eastern (MID) AF: 0.308 AC: 1766 AN: 5740

European-Non Finnish (NFE) AF: 0.387 AC: 427645 AN: 1105704

Other (OTH) AF: 0.368 AC: 22001 AN: 59790

GnomAD4 genome AF: 0.294 AC: 44719 AN: 152232 Hom.: 7874 Cov.: 34 AF XY: 0.296 AC XY: 22012 AN XY: 74416

African (AFR) AF: 0.0919 AC: 3817 AN: 41552

American (AMR) AF: 0.411 AC: 6287 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1059 AN: 3472

East Asian (EAS) AF: 0.470 AC: 2437 AN: 5180

South Asian (SAS) AF: 0.339 AC: 1635 AN: 4826

European-Finnish (FIN) AF: 0.300 AC: 3182 AN: 10596

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.370 AC: 25147 AN: 67988

Other (OTH) AF: 0.328 AC: 693 AN: 2112

Alfa AF: 0.343 Hom.: 14999

Bravo AF: 0.296

TwinsUK AF: 0.392 AC: 1455

ALSPAC AF: 0.393 AC: 1516

ESP6500AA AF: 0.0926 AC: 398

ESP6500EA AF: 0.367 AC: 3114

ExAC AF: 0.322 AC: 38663

Asia WGS AF: 0.381 AC: 1325 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;T;T;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.69	T;T;.;.;.;T
MetaRNN	Benign	0.00029	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L;.;L;L;.;.
PhyloP100		-0.14
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N
REVEL	Benign	0.047
Sift	Benign	0.15	T;T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T;T
Polyphen		0.0030	B;.;B;B;.;.
Vest4		0.055
MPC		0.14
ClinPred		0.013	T
GERP RS		-0.0015
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.097
Mutation Taster		=98/2	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: rs1801368; hg19: chr7-1976457; COSMIC: COSV56229694;