19-13905961-G-A

Variant names:

• chr19-13905961-G-A
• rs3745457
• NM_001345843.2:c.-268C>T

Variant summary

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

The NM_001345843.2(BRME1):​c.-268C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 149,260 control chromosomes in the GnomAD database, including 8,040 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 0.31 (8030 hom., cov: 30)
  • Exomes 𝑓: 0.32 (10 hom.)
• Consequence: BRME1 NM_001345843.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0220
• Publications: 5 publications found

Genes affected

BRME1 (HGNC:28153): (break repair meiotic recombinase recruitment factor 1) Predicted to be involved in meiosis I and spermatogenesis. Predicted to be located in chromosome. [provided by Alliance of Genome Resources, Apr 2022]

CC2D1A (HGNC:30237): (coiled-coil and C2 domain containing 1A) This gene encodes a transcriptional repressor that binds to a conserved 14-bp 5'-repressor element and regulates expression of the 5-hydroxytryptamine (serotonin) receptor 1A gene in neuronal cells. The DNA binding and transcriptional repressor activities of the protein are inhibited by calcium. A mutation in this gene results in a nonsyndromic form of cognitive disability (MRT3). [provided by RefSeq, Jul 2017]

CC2D1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal recessive 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRME1	NM_001345843.2	c.-268C>T		5_prime_UTR_variant	Exon 1 of 9	ENST00000586783.6	NP_001332772.2
CC2D1A	NM_017721.5	c.-481G>A		upstream_gene_variant		ENST00000318003.11	NP_060191.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRME1	ENST00000586783.6	c.-268C>T		5_prime_UTR_variant	Exon 1 of 9	5	NM_001345843.2	ENSP00000465822.1
CC2D1A	ENST00000318003.11	c.-481G>A		upstream_gene_variant		1	NM_017721.5	ENSP00000313601.6

Frequencies

GnomAD3 genomes AF: 0.307 AC: 45680 AN: 148952 Hom.: 8001 Cov.: 30

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.325 AC: 63 AN: 194 Hom.: 10 Cov.: 0 AF XY: 0.268 AC XY: 30 AN XY: 112

African (AFR) AF: 0.563 AC: 9 AN: 16

American (AMR) AF: 0.750 AC: 3 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.300 AC: 3 AN: 10

South Asian (SAS) AF: 0.250 AC: 5 AN: 20

European-Finnish (FIN) AF: 0.167 AC: 2 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.293 AC: 34 AN: 116

Other (OTH) AF: 0.438 AC: 7 AN: 16

GnomAD4 genome AF: 0.307 AC: 45757 AN: 149066 Hom.: 8030 Cov.: 30 AF XY: 0.302 AC XY: 22001 AN XY: 72888

African (AFR) AF: 0.546 AC: 21478 AN: 39336

American (AMR) AF: 0.247 AC: 3736 AN: 15134

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 491 AN: 3456

East Asian (EAS) AF: 0.279 AC: 1411 AN: 5052

South Asian (SAS) AF: 0.287 AC: 1354 AN: 4722

European-Finnish (FIN) AF: 0.165 AC: 1738 AN: 10522

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14823 AN: 67552

Other (OTH) AF: 0.273 AC: 571 AN: 2088

Alfa AF: 0.279 Hom.: 714

Asia WGS AF: 0.351 AC: 1219 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.5
DANN	Benign	0.83
PhyloP100		0.022
PromoterAI		0.0092	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3745457; hg19: chr19-14016774;