5-163473422-C-T

Position:

• chr5-163473422-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001142556.2(HMMR):​c.769C>T​(p.Gln257*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMMR NM_001142556.2 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

Genes affected

HMMR (HGNC:5012): (hyaluronan mediated motility receptor) The protein encoded by this gene is involved in cell motility. It is expressed in breast tissue and together with other proteins, it forms a complex with BRCA1 and BRCA2, thus is potentially associated with higher risk of breast cancer. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMMR	NM_001142556.2	c.769C>T	p.Gln257*	stop_gained	9/18	ENST00000393915.9	NP_001136028.1
HMMR	NM_012484.3	c.766C>T	p.Gln256*	stop_gained	9/18		NP_036616.2
HMMR	NM_012485.3	c.721C>T	p.Gln241*	stop_gained	8/17		NP_036617.2
HMMR	NM_001142557.2	c.508C>T	p.Gln170*	stop_gained	6/15		NP_001136029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMMR	ENST00000393915.9	c.769C>T	p.Gln257*	stop_gained	9/18	1	NM_001142556.2	ENSP00000377492.4
HMMR	ENST00000358715.3	c.766C>T	p.Gln256*	stop_gained	9/18	1		ENSP00000351554.3
HMMR	ENST00000353866.7	c.721C>T	p.Gln241*	stop_gained	8/17	1		ENSP00000185942.6
HMMR	ENST00000432118.6	c.508C>T	p.Gln170*	stop_gained	6/15	2		ENSP00000402673.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249304 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134906

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: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Aug 30, 2022

The c.769C>T variant is not present in 1000 Genomes, EVS, Indian Exome Database or our in-house exome database. The variant is present in gnomAD at a low frequency. The variant has not been previously reported to ClinVar, HGMD or OMIM databases in affected individuals. In-silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2, CADD etc. predicted this variant to be likely deleterious, however these predictions were not confirmed by any published functional studies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.81	D
Vest4		0.88
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs779902788; hg19: chr5-162900428;