21-29326764-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001186.4(BACH1):c.940T>C(p.Ser314Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,614,012 control chromosomes in the GnomAD database, including 238 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (112 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (126 hom.)
• Consequence: BACH1 NM_001186.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.153

Genes affected

BACH1 (HGNC:935): (BTB domain and CNC homolog 1) This gene encodes a transcription factor that belongs to the cap'n'collar type of basic region leucine zipper factor family (CNC-bZip). The encoded protein contains broad complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) domains, which is atypical of CNC-bZip family members. These BTB/POZ domains facilitate protein-protein interactions and formation of homo- and/or hetero-oligomers. When this encoded protein forms a heterodimer with MafK, it functions as a repressor of Maf recognition element (MARE) and transcription is repressed. Multiple alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019133389).
• BP6: Variant 21-29326764-T-C is Benign according to our data. Variant chr21-29326764-T-C is described in ClinVar as [Benign]. Clinvar id is 3055804.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BACH1	NM_001186.4	c.940T>C	p.Ser314Pro	missense_variant	3/5	ENST00000286800.8
BACH1	NM_206866.3	c.940T>C	p.Ser314Pro	missense_variant	3/5
BACH1	NR_027655.3	n.1119T>C		non_coding_transcript_exon_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BACH1	ENST00000286800.8	c.940T>C	p.Ser314Pro	missense_variant	3/5	1	NM_001186.4	P1
BACH1	ENST00000399921.5	c.940T>C	p.Ser314Pro	missense_variant	3/5	1		P1

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3452 AN: 152192 Hom.: 111 Cov.: 33

Gnomad AFR AF: 0.0787

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00572 AC: 1434 AN: 250848 Hom.: 55 AF XY: 0.00427 AC XY: 580 AN XY: 135752

Gnomad AFR exome AF: 0.0798

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00220 AC: 3209 AN: 1461702 Hom.: 126 Cov.: 31 AF XY: 0.00190 AC XY: 1383 AN XY: 727154

Gnomad4 AFR exome AF: 0.0770

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.00543

GnomAD4 genome AF: 0.0227 AC: 3457 AN: 152310 Hom.: 112 Cov.: 33 AF XY: 0.0218 AC XY: 1622 AN XY: 74476

Gnomad4 AFR AF: 0.0786

Gnomad4 AMR AF: 0.00921

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00427 Hom.: 42

Bravo AF: 0.0263

ESP6500AA AF: 0.0760 AC: 335

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00716 AC: 869

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

BACH1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	13
Dann	Benign	0.95
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.82	N;N
REVEL	Benign	0.034
Sift	Benign	0.18	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.0050	B;B
Vest4		0.17
MVP		0.70
MPC		0.12
ClinPred		0.0014	T
GERP RS		1.7
Varity_R		0.062
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs35474725; hg19: chr21-30699085;