7-1816238-A-G

Variant names:

• chr7-1816238-A-G
• rs374595397
• NM_001013836.2:c.1999-10T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001013836.2(MAD1L1):​c.1999-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,608,916 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (50 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (33 hom.)
• Consequence: MAD1L1 NM_001013836.2 intron
• Scores: Splicing: ADA: 0.00004909
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.173
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-1816238-A-G is Benign according to our data. Variant chr7-1816238-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 789755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0135 (2058/152292) while in subpopulation AFR AF = 0.0464 (1926/41544). AF 95% confidence interval is 0.0446. There are 50 homozygotes in GnomAd4. There are 989 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013836.2. 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
	MAD1L1	NM_001013836.2	MANE Select	c.1999-10T>C		intron	N/A	NP_001013858.1	Q9Y6D9-1
	MAD1L1	NM_001013837.2		c.1999-10T>C		intron	N/A	NP_001013859.1	Q9Y6D9-1
	MAD1L1	NM_001304523.2		c.1999-10T>C		intron	N/A	NP_001291452.1	Q9Y6D9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAD1L1	ENST00000265854.12	TSL:1 MANE Select	c.1999-10T>C		intron	N/A	ENSP00000265854.7	Q9Y6D9-1
	MAD1L1	ENST00000406869.5	TSL:1	c.1999-10T>C		intron	N/A	ENSP00000385334.1	Q9Y6D9-1
	ENSG00000286192	ENST00000651235.1		n.*4759-10T>C		intron	N/A	ENSP00000498895.1	A0A3B3ITW8

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2051 AN: 152174 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.0463

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00549

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.000118 AC: 29 AN: 245430 AF XY: 0.0000749

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00113 AC: 1648 AN: 1456624 Hom.: 33 Cov.: 31 AF XY: 0.000953 AC XY: 690 AN XY: 724154

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0352 AC: 1151 AN: 32732

American (AMR) AF: 0.00240 AC: 107 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52882

Middle Eastern (MID) AF: 0.00396 AC: 21 AN: 5298

European-Non Finnish (NFE) AF: 0.000178 AC: 198 AN: 1109542

Other (OTH) AF: 0.00278 AC: 167 AN: 60108

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0135 AC: 2058 AN: 152292 Hom.: 50 Cov.: 33 AF XY: 0.0133 AC XY: 989 AN XY: 74478

African (AFR) AF: 0.0464 AC: 1926 AN: 41544

American (AMR) AF: 0.00549 AC: 84 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68012

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00632 Hom.: 4

Bravo AF: 0.0150

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.52
DANN	Benign	0.32
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.0
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: rs374595397; hg19: chr7-1855874;