5-163483120-C-G

Variant names:

• chr5-163483120-C-G
• rs200981355
• NM_001142556.2:c.1633C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001142556.2(HMMR):​c.1633C>G​(p.Leu545Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L545F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HMMR NM_001142556.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.53
• Publications: 4 publications found

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]

HMMR-AS1 (HGNC:49149): (HMMR antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31868377).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142556.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMMR	NM_001142556.2	MANE Select	c.1633C>G	p.Leu545Val	missense	Exon 14 of 18	NP_001136028.1	O75330-3
	HMMR	NM_012484.3		c.1630C>G	p.Leu544Val	missense	Exon 14 of 18	NP_036616.2	O75330-1
	HMMR	NM_012485.3		c.1585C>G	p.Leu529Val	missense	Exon 13 of 17	NP_036617.2	O75330-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMMR	ENST00000393915.9	TSL:1 MANE Select	c.1633C>G	p.Leu545Val	missense	Exon 14 of 18	ENSP00000377492.4	O75330-3
	HMMR	ENST00000358715.3	TSL:1	c.1630C>G	p.Leu544Val	missense	Exon 14 of 18	ENSP00000351554.3	O75330-1
	HMMR	ENST00000353866.7	TSL:1	c.1585C>G	p.Leu529Val	missense	Exon 13 of 17	ENSP00000185942.6	O75330-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249196 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460342 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726550

African (AFR) AF: 0.00 AC: 0 AN: 33330

American (AMR) AF: 0.00 AC: 0 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111396

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Benign	0.034	D
Sift4G	Benign	0.22	T
Polyphen		0.99	D
Vest4		0.43
MutPred		0.26		Gain of methylation at K545 (P = 0.0343)
MVP		0.80
MPC		0.36
ClinPred		0.80	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.33
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs200981355; hg19: chr5-162910126;