19-17276560-G-C

Variant names:

• chr19-17276560-G-C
• rs201681717
• NM_014173.4:c.635G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014173.4(BABAM1):​c.635G>C​(p.Arg212Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,452,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: BABAM1 NM_014173.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.09

Genes affected

BABAM1 (HGNC:25008): (BRISC and BRCA1 A complex member 1) Involved in several processes, including mitotic G2 DNA damage checkpoint signaling; positive regulation of DNA repair; and protein K63-linked deubiquitination. Located in cytosol and nuclear body. Part of BRCA1-A complex and BRISC complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000269307 (HGNC:):

USHBP1 (HGNC:24058): (USH1 protein network component harmonin binding protein 1) Enables PDZ domain binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BABAM1	NM_014173.4	c.635G>C	p.Arg212Pro	missense_variant	Exon 7 of 9	ENST00000598188.6	NP_054892.2
BABAM1	NM_001033549.3	c.635G>C	p.Arg212Pro	missense_variant	Exon 7 of 9		NP_001028721.1
BABAM1	NM_001288756.2	c.635G>C	p.Arg212Pro	missense_variant	Exon 7 of 9		NP_001275685.1
BABAM1	NM_001288757.2	c.410G>C	p.Arg137Pro	missense_variant	Exon 4 of 6		NP_001275686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BABAM1	ENST00000598188.6	c.635G>C	p.Arg212Pro	missense_variant	Exon 7 of 9	1	NM_014173.4	ENSP00000471605.1
ENSG00000269307	ENST00000596542.1	n.*249G>C		non_coding_transcript_exon_variant	Exon 6 of 10	2		ENSP00000469159.2
ENSG00000269307	ENST00000596542.1	n.*249G>C		3_prime_UTR_variant	Exon 6 of 10	2		ENSP00000469159.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000429 AC: 1 AN: 233262 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126464

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000952

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1452886 Hom.: 0 Cov.: 32 AF XY: 0.00000416 AC XY: 3 AN XY: 721748

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.635G>C (p.R212P) alteration is located in exon 7 (coding exon 6) of the BABAM1 gene. This alteration results from a G to C substitution at nucleotide position 635, causing the arginine (R) at amino acid position 212 to be replaced by a proline (P). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;T;D;D;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;.;D;.;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.8	M;.;M;M;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.9	.;.;D;.;.;.
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	.;.;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.97
MutPred		0.86		Gain of glycosylation at T213 (P = 0.0181);.;Gain of glycosylation at T213 (P = 0.0181);Gain of glycosylation at T213 (P = 0.0181);.;Gain of glycosylation at T213 (P = 0.0181);
MVP		0.84
MPC		1.2
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201681717; hg19: chr19-17387369;