5-163469686-C-G

Variant names:

• chr5-163469686-C-G
• rs778640242
• NM_001142556.2:c.319C>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001142556.2(HMMR):​c.319C>G​(p.Gln107Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000868 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: HMMR NM_001142556.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29986554).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMMR	NM_001142556.2	c.319C>G	p.Gln107Glu	missense_variant	Exon 5 of 18	ENST00000393915.9	NP_001136028.1
HMMR	NM_012484.3	c.316C>G	p.Gln106Glu	missense_variant	Exon 5 of 18		NP_036616.2
HMMR	NM_012485.3	c.271C>G	p.Gln91Glu	missense_variant	Exon 4 of 17		NP_036617.2
HMMR	NM_001142557.2	c.58C>G	p.Gln20Glu	missense_variant	Exon 2 of 15		NP_001136029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMMR	ENST00000393915.9	c.319C>G	p.Gln107Glu	missense_variant	Exon 5 of 18	1	NM_001142556.2	ENSP00000377492.4
HMMR	ENST00000520345	c.-27C>G		5_prime_UTR_variant	Exon 4 of 6	2		ENSP00000428481.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251294 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135826

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: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461740 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727184

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: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast Uncertain:1

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.319C>G (p.Gln107Glu) variant in HMMR gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Gln107Glu variant is present with allele frequency of 0.002% in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change p.Gln107Glu in HMMR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gln at position 107 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	.;.;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Uncertain	0.0073	D
MutationAssessor	Uncertain	2.5	.;.;.;M
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.026	D;D;D;D
Sift4G	Benign	0.22	T;T;D;T
Polyphen		0.97	D;D;D;D
Vest4		0.33
MutPred		0.17		.;.;.;Loss of MoRF binding (P = 0.097);
MVP		0.87
MPC		0.24
ClinPred		0.40	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs778640242; hg19: chr5-162896692;